Antidiabetic agents

ABSTRACT

A compound of the formula  
                 
wherein 
         R 1  is:  
                 
   R 5  is:  
                 
 
and n, m, Z, R 8 , R 9 , R 10  and R 11  are as defined herein, useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly, myocardial ischemia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §121 to U.S. Ser. No.10/368,916, filed Feb. 19, 2003, now allowed, which claims priority to.U.S. Provisional Ser. No. 60/360,913, filed Feb. 28, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to substituted 1H-(indole-2-carboxamidesand 6H-thieno[2,3-b]pyrrole-5-carboxamides which are antidiabetic agentsand as such are useful in the treatment of diabetes, insulin resistance,diabetic neuropathy, diabetic nephropathy, diabetic retinopathy,cataracts, hyperglycemia, hypercholesterolemia, hypertension,hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia,particularly myocardial ischemia.

This invention also relates to a method of using such compounds in thetreatment of the above diseases in mammals, especially humans, and tothe pharmaceutical compositions useful therefor.

In spite of the early discovery of insulin and its subsequent widespreaduse in the treatment of diabetes, and the later discovery of and use ofsulfonylureas, biguanides and thiazolidinediones, such as troglitazone,rosiglitazone or pioglitazone, as oral hypoglycemic agents, thetreatment of diabetes remains less than satisfactory.

The use of insulin requires multiple daily doses, usually by selfinjection. Determination of the proper dosage of insulin requiresfrequent estimations of the sugar in urine or blood. The administrationof an excess dose of insulin causes hypoglycemia, with effects rangingfrom mild abnormalities in blood glucose to coma, or even death.Treatment of non-insulin dependent diabetes mellitus (Type II diabetes,NIDDM) usually consists of a combination of diet, exercise, oralhypoglycemic agents, e.g., thiazolidinediones, and in more severe cases,insulin. However, the clinically available hypoglycemic agents can haveside effects that limit their use, or an agent may not be effective witha particular patient. In the case of insulin dependent diabetes mellitus(Type I), insulin is usually the primary course of therapy. Hypoglycemicagents that have fewer side effects or succeed where others fail areneeded.

Atherosclerosis, a disease of the arteries, is recognized to be theleading cause of death in the United States and Western Europe. Thepathological sequence leading to atherosclerosis and occlusive heartdisease is well known. The earliest stage in this sequence is theformation of “fatty streaks” in the carotid, coronary and cerebralarteries and in the aorta. These lesions are yellow in color due to thepresence of lipid deposits found principally within smooth-muscle cellsand in macrophages of the intima layer of the arteries and aorta.Further, it is postulated that most of the cholesterol found within thefatty streaks, in turn, give rise to development of the “fibrousplaque,” which consists of accumulated intimal smooth muscle cells ladenwith lipid and surrounded by extra-cellular lipid, collagen, elastin andproteoglycans. The cells plus matrix form a fibrous cap that covers adeeper deposit of cell debris and more extra cellular lipid. The lipidis primarily free and esterified cholesterol. The fibrous plaque formsslowly, and is likely in time to become calcified and necrotic,advancing to the “complicated lesion,” which accounts for the arterialocclusion and tendency toward mural thrombosis and arterial muscle spasmthat characterize advanced atherosclerosis.

Epidemiological evidence has firmly established hyperlipidemia as aprimary risk factor in causing cardiovascular disease (CVD) due toatherosclerosis. In recent years, leaders of the medical profession haveplaced renewed emphasis on lowering plasma cholesterol levels, and lowdensity lipoprotein cholesterol in particular, as an essential step inprevention of CVD. The upper limits of “normal” are now known to besignificantly lower than heretofore appreciated. As a result, largesegments of Western populations are now realized to be at particularlyhigh risk. Such independent risk factors include glucose intolerance,left ventricular hypertrophy, hypertension, and being of the male sex.Cardiovascular disease is especially prevalent among diabetic subjects,at least in part because of the existence of multiple independent riskfactors in this population. Successful treatment of hyperlipidemia inthe general population, and in diabetic subjects in particular, istherefore of exceptional medical importance.

Hypertension (or high blood pressure) is a condition which occurs in thehuman population as a secondary symptom to various other disorders suchas renal artery stenosis, pheochromocytoma or endocrine disorders.However, hypertension is also evidenced in many patients in whom thecausative agent or disorder is unknown. While such “essential”hypertension is often associated with disorders such as obesity,diabetes and hypertriglyceridemia, the relationship between thesedisorders has not been elucidated. Additionally, many patients displaythe symptoms of high blood pressure in the complete absence of any othersigns of disease or disorder.

It is known that hypertension can directly lead to heart failure, renalfailure and stroke (brain hemorrhaging). These conditions are capable ofcausing death in a patient. Hypertension can also contribute to thedevelopment of atherosclerosis and coronary disease. These conditionsgradually weaken a patient and can lead to death.

The exact cause of essential hypertension is unknown, though a number offactors are believed to contribute to the onset of the disease. Amongsuch factors are stress, uncontrolled emotions, unregulated hormonerelease (the renin, angiotensin, aldosterone system), excessive salt andwater due to kidney malfunction, wall thickening and hypertrophy of thevasculature resulting in constricted blood vessels and genetic factors.

The treatment of essential hypertension has been undertaken bearing theforegoing factors in mind. Thus, a broad range of beta-blockers,vasoconstrictors, angiotensin converting enzyme inhibitors and the likehave been developed and marketed as antihypertensives. The treatment ofhypertension utilizing these compounds has proven beneficial in theprevention of short-interval deaths such as heart failure, renal failureand brain hemorrhaging. However, the development of atherosclerosis orheart disease due to hypertension over a long period of time remains aproblem. This implies that although high blood pressure is beingreduced, the underlying cause of essential hypertension is notresponding to this treatment.

Hypertension has been associated with elevated blood insulin levels, acondition known as hyperinsulinemia. Insulin, a peptide hormone whoseprimary actions are to promote glucose utilization, protein synthesisand the formation and storage of neutral lipids, also acts to promotevascular cell growth and increase renal sodium retention, among otherthings. These latter functions can be accomplished without affectingglucose levels and are known causes of hypertension. Peripheralvasculature growth, for example, can cause constriction of peripheralcapillaries while sodium retention increases blood volume. Thus, thelowering of insulin levels in hyperinsulinemics can prevent abnormalvascular growth and renal sodium retention caused by high insulin levelsand thereby alleviate hypertension.

Cardiac hypertrophy is a significant risk factor in the development ofsudden death, myocardial infarction, and congestive heart failure. Thesecardiac events are due, at least in part, to increased susceptibility tomyocardial injury after ischemia and reperfusion that can occur inout-patient as well as perioperative settings. There is an unmet medicalneed to prevent or minimize adverse myocardial perioperative outcomes,particularly perioperative myocardial infarction. Both non-cardiac andcardiac surgery are associated with substantial risks for myocardialinfarction or death. Some 7 million patients undergoing non-cardiacsurgery are considered to be at risk, with incidences of perioperativedeath and serious cardiac complications as high as 20-25% in someseries. In addition, of the 400,000 patients undergoing coronary by-passsurgery annually, perioperative myocardial infarction is estimated tooccur in 5% and death in 1-2%. There is currently no marketed drugtherapy in this area which reduces damage to cardiac tissue fromperioperative myocardial ischemia or enhances cardiac resistance toischemic episodes. Such a therapy is anticipated to be life-saving andreduce hospitalizations, enhance quality of life and reduce overallhealth care costs of high risk patients. The mechanism(s) responsiblefor the myocardial injury observed after ischemia and reperfusion is notfully understood. It has been reported (M. F. Allard, et al., Am. J.Physiol., 267: H66-H74 (1994)) that “pre ischemic glycogen reduction . .. is associated with improved post ischemic left ventricular functionalrecovery in hypertrophied rat hearts”.

In addition to myocardial ischemia, other tissues can undergo ischemiaand be damaged resulting in serious problems for the patient. Examplesof such tissues include cardiac, brain, liver, kidney, lung, gut,skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue,the vasculature, or intestinal tissue.

Hepatic glucose production is an important target for NIDDM therapy. Theliver is the major regulator of plasma glucose levels in the postabsorptive (fasted) state, and the rate of hepatic glucose production inNIDDM patients is significantly elevated relative to normal individuals.Likewise, in the postprandial (fed) state, where the liver has aproportionately smaller role in the total plasma glucose supply, hepaticglucose production is abnormally high in NIDDM patients.

Glycogenolysis is an important target for interruption of hepaticglucose production. The liver produces glucose by glycogenolysis(breakdown of the glucose polymer glycogen) and gluconeogenesis(synthesis of glucose from 2- and 3-carbon precursors). Several lines ofevidence indicate that glycogenolysis may make an important contributionto hepatic glucose output in NIDDM. First, in normal post absorptiveman, up to 75% of hepatic glucose production is estimated to result fromglycogenolysis. Second, patients having liver glycogen storage diseases,including Hers' disease (glycogen phosphorylase deficiency), displayepisodic hypoglycemia. These observations suggest that glycogenolysismay be a significant process for hepatic glucose production.

Glycogenolysis is catalyzed in liver, muscle, and brain bytissue-specific isoforms of the enzyme glycogen phosphorylase. Thisenzyme cleaves the glycogen macromolecule to release glucose-1-phosphateand a new shortened glycogen macromolecule. Several types of glycogenphosphorylase inhibitors have been reported to date: glucose and glucoseanalogs [Martin, J. L. et al., Biochemistry, 30:10101 (1991)]; caffeineand other purine analogs [Kasvinsky, P. J. et al., J. Biol. Chem., 253:3343-3351 and 9102-9106 (1978)]; substitutedN-(indole-2-carbonyl)-amides [PCT Publication Number WO 96/39385]; andsubstituted N-(indole-2-carbonyl)-glycinamides [PCT Publication NumberWO 96/393841. These compounds and glycogen phosphorylase inhibitors ingeneral, have been postulated to be of use for the treatment of NIDDM bydecreasing hepatic glucose production and lowering glycemia. [Blundell,T. B. et al., Diabetologia, 35: Suppl. 2, 569-576 (1992) and Martin etal., Biochemistry, 30: 10101 (1991)].

Myocardial ischemic injury can occur in outpatient as well as inperioperative settings and can lead to the development of sudden death,myocardial infarction or congestive heart failure. There is an unmetmedical need to prevent or minimize myocardial ischemic injury,particularly perioperative myocardial infarction. Such a therapy isanticipated to be life-saving and reduce hospitalizations, enhancequality of life and reduce overall health care costs of high riskpatients.

Although there are a variety of hyperglycemia, hypercholesterolemia,hypertension, hyperlipidemia, atherosclerosis and tissue ischemiatherapies, there is a continuing need and a continuing search in thisfield of art for alternative therapies.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula

or the pharmaceutically acceptable salt thereof; wherein

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

Z is oxygen or sulfur;

R¹ is

wherein the dashed lines represent optional double bonds;

a is 1, 2 or 3;

each R² is independently hydrogen, halo, hydroxy, amino, nitro,(C₁-C₆)alkoxy, cyano, C(O)H or (C₁-C₆)alkyl optionally substituted byone to three fluoro atoms;

R³ is hydrogen, halo, cyano, (C₁-C₆)alkyl or (C₁-C₃)alkynyl;

R⁴ is hydrogen, halo, cyano or (C₁-C₆)alkyl;

R⁵ is

wherein the dashed lines represent optional double bonds;

A, B and E are each independently nitrogen or CR15;

X and Y are each independently CH₂, oxygen, S(O)_(d) wherein d is 0, 1or 2; nitrogen or NR¹⁶;

R⁸, R⁹, R¹⁰ and R¹¹ are each independently hydrogen or (C₁-C₆)alkyl;

R¹² is hydrogen, HC(O)(C₀-C₆)alkyl, carboxy(C₀-C₃)alkyl,R¹⁷R¹⁸N—C(O)—(C₁-C₃)alkyl, hydroxy(C₁-C₃)alkyl, R¹⁷(C₁-C₃)alkyl,R¹⁷R¹⁸N(C₀-C₃)alkyl, (C₁-C₆)alkyl-C(O)—NH, (C₆-C₁₀)aryl-C(O)—NH,(C₆-C₁₀)aryl(C₁-C₆)alkyl-C(O)—NH, (C₂-C₉)heteroaryl(C₁-C₆)alkyl-C(O)—NH,(C₁-C₆)alkylaminocarbonylamino, (C₆-C₁₀)arylaminocarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminocarbonylamino,(C₁-C₆)alkylsulfonylamino, (C₆-C₁₀)aryl(C₁-C₆)alkylsulfonylamino,(C₂-C₆)heteroarylsulfonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylN((C₁-C₆)alkyl), (C₆-C₁₀)aryl(C₁-C₆)alkylsulfonyl N((C₁-C₆)alkyl),(C₂-C₉)heteroarylsulfonyl N((C₁-C₆)alkyl),(C₂-C₉)heteroaryl(C₁-C₆)alkylsulfonyl N((C₁-C₆)alkyl),(C₃-C₇)cycloalkylamino, ((C₃-C₇)cycloalkyl)₂amino,(C₃-C₇)cycloalkylcarbonylamino,(C₆-C₁₀)aryl(C₃-C₇)cycloalkylcarbonylamino,(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylcarbonylamino,(C₃-C₇)cycloalkylaminocarbonylamino,(C₆-C₁₀)aryl(C₃-C₇)cycloalkylaminocarbonylamino,(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylaminocarbonylamino,(C₃-C₇)cycloalkylsulfonylamino,(C₆-C₁₀)aryl(C₃-C₇)cycloalkylsulfonylamino,(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylsulfonylamino,(C₃-C₇)cycloalkylsulfonyl N((C₃-C₇)cycloalkyl),(C₆-C₁₀,)aryl(C₃-C₇)cycloalkylsulfonyl N((C₃-C₇)cycloalkyl,(C₂-C₉)heteroarylsulfonyl N((C₃-C₇)cycloalkyl),(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylsulfonyl N((C₃-C₇)cycloalkyl),(C₁-C₆)alkyl S(O)_(c), (C₃-C₇)cycloalkyl S(O)_(c),(C₆-C₁₀)aryl(C₁-C₆)alkyl S(O)_(c), (C₆-C₁₀)aryl S(O)_(c),(C₁-C₆)alkylamino S(O)_(c), (C₁-C₆)arylamino S(O)_(c),(C₆-C₁₀)arylC₁-C₆)alkylamino S(O)_(c), wherein c is 0, 1 or 2;

R¹³ is hydrogen or (C₁-C₆)alkyl;

R¹⁴ is hydrogen, hydroxy, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy or NR¹⁷R¹⁸;

R¹⁵ is hydrogen, (C₁-C₆)alkylcarbonylcarboxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkyl piperazinylcarbonyl or piperidinylcarbonyl;

R¹⁶ is hydrogen, HCO, (C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, piperidinyl(C₁-C₆)alkylcarbonyl; (C₁-C₆)acyl;piperidinyl carbonyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkylcarbonyl or morpholinyl(C₁-C₆)alkylcarbony;

R¹⁷ and R¹⁸ are each independently hydrogen, (C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkyl and (C₂-C₉)heteroaryl(C₁-C₆)alkyl.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term “alkoxy”, as used herein, includes O-alkyl groups wherein“alkyl” is defined above.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3substituents selected from the group consisting of fluoro, chloro,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy and (C₁-C₆)alkyl.

The term “heteroaryl”, as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic heterocycle byremoval of one hydrogen, such as furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,benzofuryl, benzothienyl, indolyl, isoindolyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl,quinazolinyl, quinoxalinyl, thienopyrrolyl or azaindolyl, optionallysubstituted by 1 to 3 substituents selected from the group consisting offluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy and (C₁-C₆)alkyl.

Preferred compounds of formula I include those wherein R¹ is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms.

Preferred compounds of formula I include those wherein n is 0, 1, 2 or3; m is 0, 1, 2 or 3; and Z is oxygen.

Preferred compounds of formula I include those wherein R⁵ is

wherein A, B and E are CR⁵;

X is oxygen or nitrogen;

Y is oxygen or NR¹⁶;

R¹² is hydrogen, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl or carboxy;

R¹⁵ is hydrogen, (C₁-C₆)alkylcarbonylcarboxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkyl piperazinylcarbonyl or piperidinylcarbonyl;

R¹⁶ is HCO, (C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,carboxy(C₁-C₃)alkyl, piperidinyl(C₁-C₆)alkylcarbonyl; (C₁-C₆)acyl;piperidinyl carbonyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkylcarbonyl or morpholinyl(C₁-C₆)alkylcarbonyl.

Other preferred compounds of formula I include those wherein R⁵ is

wherein A is CR¹⁵;

B and E are each independently CR¹⁵ or nitrogen; and

X and Y are each independently nitrogen or CH₂.

Other preferred compounds of formula I include those wherein R⁵ is

wherein A is CR¹⁵:

B and E are each independently oxygen or nitrogen; and

X and Y are each independently nitrogen or CH₂.

Most preferred compounds of formula I include those wherein R¹ is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms; n is0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R⁵ is

wherein A, B and E are CR¹⁵;

X is oxygen or nitrogen;

Y is oxygen or NR¹⁶;

R¹² is hydrogen, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl or carboxy;

R¹⁵ is hydrogen, (C₁-C₆)alkylcarbonylcarboxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkyl piperazinylcarbonyl or piperidinylcarbonyl;

R¹⁶ is HCO, (C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, piperidinyl(C₁-C₆)alkylcarbonyl; (C₁-C₆)acyl;piperidinyl carbonyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,halo(C₁-C₆)alkylcarbonyl or morpholinyl(C₁-C₆)alkylcarbonyl.

Most preferred compounds of formula I include those wherein R¹ is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms; n is0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R⁵ is

wherein A is CR¹⁵;

B and E are each independently CR⁵ or nitrogen; and

X and Y are each independently nitrogen or CH₂.

Most preferred compounds of formula I include those wherein R¹ is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms; n is0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R⁵ is

wherein A is CR¹⁵;

B and E are each independently CR¹⁵ or nitrogen; and

X and Y are each independently nitrogen or CH₂.

Specific preferred compounds of formula I include those wherein saidcompound is selected from the group consisting of:

5-Chloro-1H-indole-2-carboxylic acid(4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid(9-methanesulfonylamino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

{[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylamino}-aceticacid ethyl ester;

{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-4-hydroxymethyl-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-aceticacid;

5-Chloro-1H-indole-2-carboxylic acid(9-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;

{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-aceticacid;

5-Methyl-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid{9-[2-(3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;

5-Chloro-1H-indole-2-carboxylic acid[4-(piperidine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide:

5-Chloro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid(3,5-dichloro-4-hydroxy-phenyl)-amide;

5-Fluoro-1H-indole-2-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;

5-Chloro-1H-indole-2-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid(9-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;

2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid;

5-Chloro-1H-indole-2-carboxylic acid (3-hydroxy-4-methoxy-phenyl)-amide;

5-Chloro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

5-Methyl-1H-indole-2-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid(9-dimethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid[9-(2-oxo-2-pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide:

5-Bromo-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

5-Methyl-1H-indole-2-carboxylic acid(2,3,4,5-tetrahydro,-benzo[b]dioxocin-8-yl)-amide;

8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-carboxylicacid;

5-Methyl-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo-[b][1,4]dioxepin-7-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid[9-(3,4-dihydroxy-pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;

5-Chloro-1H-indole-2-carboxylic acid[4-(4-methyl-piperazine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;

1H-Indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

1H-Indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;

5-Chloro-1H-indole-2-carboxylic acid[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;

5-Fluoro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)amide;

5-Chloro-1H-indole-2-carboxylic acid {9-[(2-hydroxy-ethylcarbamoyl)-methyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;

2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid methyl ester;

5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethyl)-4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;

1H-Indole-2-carboxylic acid(2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide; and

5-Fluoro-1H-indole-2-carboxylic acid(2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide.

Also provided are pharmaceutical compositions comprising a compound ofFormula I, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating or preventing atherosclerosis, themethods comprising the step of administering to a patient havingatherosclerosis or at risk of having atherosclerosis a therapeuticallyeffective amount of a compound of Formula I, stereoisomers,pharmaceutically acceptable salts and prodrugs thereof, andpharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating diabetes, the methods comprisingthe step of administering to a patient having diabetes a therapeuticallyeffective amount of a compound of Formula I, stereoisomers,pharmaceutically acceptable salts and prodrugs thereof, andpharmaceutically acceptable salts of the prodrug.

In a preferred embodiment of the methods of treating diabetes, thediabetes is non-insulin dependent diabetes mellitus (Type II).

In another preferred embodiment of the methods of treating diabetes, thediabetes is insulin dependent diabetes mellitus (Type I).

Also provided are methods of treating insulin resistance, the methodscomprising the step of administering to a patient having insulinresistance a therapeutically effective amount of a compound of FormulaI, stereoisomers. pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating diabetic nephropathy, the methodscomprising the step of administering to a patient having diabeticneuropathy a therapeutically effective amount of a compound of FormulaI, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating diabetic nephropathy, the methodscomprising the step of administering to a patient having diabeticnephropathy a therapeutically effective amount of a compound of FormulaI, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating diabetic retinopathy, the methodscomprising the step of administering to a patient having diabeticretinopathy a therapeutically effective amount of a compound of FormulaI, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating cataracts, the methods comprisingthe step of administering to a patient having cataracts atherapeutically effective amount of a compound of Formula I,stereoisomers, pharmaceutically acceptable salts and prodrugs thereofand pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating or preventinghypercholestereolemia, the methods comprising the step of administeringto a patient having hypercholesterolemia or at risk of havinghypercholesterolemia a therapeutically effective amount of a compound ofFormula I, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating or preventinghypertriglyceridemia, the methods comprising the step of administeringto a patient having hypertriglyceridemia or at risk of havinghypertriglyceridemia a therapeutically effective amount of a compound ofFormula I, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating or preventing hyperlipidemia, themethods comprising the step of administering to a patient havinghyperlipidemia or at risk of having hyperlipidemia a therapeuticallyeffective amount of a compound of Formula I, stereoisomers,pharmaceutically acceptable salts and prodrugs thereof, andpharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating hyperglycemia, the methodscomprising the step of administering to a patient having hyperglycemiaor at risk of having hyperglycemia therapeutically effective amount of acompound of Formula I, stereoisomers, pharmaceutically acceptable saltsand prodrugs thereof, and pharmaceutically acceptable salts of theprodrugs.

Also provided are methods of treating hypertension, the methodscomprising the step of administering to a patient having hypertension orat risk of having hypertension a therapeutically effective amount of acompound of Formula I, stereoisomers, pharmaceutically acceptable saltsand prodrugs thereof, and pharmaceutically acceptable salts of theprodrugs.

Also provided are methods of treating or preventing tissue ischemia, themethods comprising the step of administering to a patient having tissueischemia or at risk of having tissue ischemia a therapeuticallyeffective amount of a compound of Formula I, stereoisomers,pharmaceutically acceptable salts and prodrugs thereof, andpharmaceutically acceptable salts of the prodrugs.

Also provided are methods of treating or preventing myocardial ischemia,the methods comprising the step of administering to a patient havingmyocardial ischemia or at risk of having myocardial ischemia atherapeutically effective amount of a compound of Formula I,stereoisomers, pharmaceutically acceptable salts and prodrugs thereof,and pharmaceutically acceptable salts of the prodrugs.

Also provided are methods of inhibiting glycogen phosphorylase, themethods comprising the step of administering to a patient in need ofglycogen phosphorylase inhibition, a glycogen phosphorylase inhibitingamount of a compound of Formula I, stereoisomers, pharmaceuticallyacceptable salts and prodrugs thereof, and pharmaceutically acceptablesalts of the prodrugs.

Also provided are kits for the treatment of diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, or cataracts in a patient having diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, or cataracts, the kits comprising:

-   a) a first pharmaceutical composition comprising a compound of    Formula I, stereoisomers, pharmaceutically acceptable salts and    prodrugs of the compounds of Formula I, and pharmaceutically    acceptable salts of the prodrugs;-   b) a second pharmaceutical composition comprising a second compound    useful for the treatment of diabetes, insulin resistance, diabetic    neuropathy, diabetic nephropathy, diabetic retinopathy, or    cataracts; and-   c) a container for containing the first and second compositions.

In a preferred embodiment of the kits, the second compound is selectedfrom:

-   insulin and insulin analogs;-   GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH₂;-   sulfonylureas and analogs;-   biguanides;-   α2-antagonists;-   imidazolines;-   glitazones (thiazolidinediones);-   PPAR-gamma agonists;-   fatty acid oxidation inhibitors;-   α-glucosidase inhibitors;-   β-agonists;-   phosphodiesterase Inhibitors;-   lipid-lowering agents:-   antiobesity agents-   vanadate, vanadium complexes and peroxovanadium complexes;-   amylin antagonists;-   glucagon antagonists;-   gluconeogenesis inhibitors;-   somatostatin analogs and antagonists; and-   antilipolytic agents.

In another preferred embodiment of the kits, the second compound isselected from LysPro insulin, GLP-1 (7-37) (insulinotropin), GLP-1(7-36)-NH₂, chlorpropamide, glibenclamide, tolbutamide, tolazamide,acetohexamide, glypizide, glimepiride, repaglinide, meglitinide;mefformin, phenformin, buformin, midaglizole, isaglidole, deriglidole,idazoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone,englitazone, troglitazone, darglitazone, rosiglitazone, clomoxir,etomoxir, acarbose, miglitol, emiglitate, voglibose, MDL-25,637,camiglibose, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL316,243, L-386,398; benfluorex, fenfluramine, Naglivan®, acipimox, WAG994, Symlin™, AC2993 and nateglinide.

In still another preferred embodiment of the kits, the second compoundis selected from insulin, sulfonylureas, biguanides, andthiazolidinediones.

Also provided are kits for the treatment of diabetes, insulin resistancediabetic neuropathy, diabetic nephropathy, diabetic retinopathy,cataracts, hyperglycemia, hypercholesterolemia, hypertension,hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia ina patient having diabetes, insulin resistance, diabetic neuropathy,diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia,hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia,atherosclerosis, or tissue ischemia, the kits comprising:

-   a) a first pharmaceutical composition comprising a compound of    Formula I, stereoisomers, pharmaceutically acceptable salts and    prodrugs of the compounds of Formula I, and pharmaceutically    acceptable salts of the prodrugs;-   b) a second pharmaceutical composition comprising a second compound    useful for the treatment of diabetes, insulin resistance, diabetic    neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts,    hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia,    hyperlipidemia, atherosclerosis, or tissue ischemia; and-   c) a container for containing the first and second compositions.

Also provided are methods of treating diabetes, insulin resistance,diabetic neuropathy, diabetic nephropathy, diabetic retinopathy,cataracts, hyperglycemia, hypercholesterolemia, hypertension,hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia,the method comprising the step of administering to a patient havingdiabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy,diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia,hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, ortissue ischemia, a therapeutically effective amount of a compound ofFormula I, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs incombination with at least one additional compound useful for thetreatment of diabetes, insulin resistance, diabetic neuropathy, diabeticnephropathy, diabetic retinopathy, cataracts, hyperglycemia,hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia,atherosclerosis, or tissue ischemia.

Also provided are pharmaceutical compositions comprising a compound ofFormula I, stereoisomers, pharmaceutically acceptable salts and prodrugsthereof, and pharmaceutically acceptable salts of the prodrugs and atleast one additional compound useful to treat diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, cataracts, hyperglycemia, hypercholesterolemia,hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, ortissue ischemia.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated a, n, m,A, B, E, R², R⁵, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ in the reactionSchemes and the discussion that follow are defined as above.

In reaction 1 of Preparation A, the diol compound of formula XV isconverted to the corresponding compound of formula XIV by reacting XVwith a compound of the formula, Br—CHR¹²—CHR¹³—CHR¹⁴—Cl, in the presenceof potassium carbonate and a polar protic solvent, such asdimethylformamide. The reaction is stirred at a temperature betweenabout 25° C. to about 100° C., preferably about 100° C., for a timeperiod between about 1 hours to about 14 hours, preferably about 12hours.

In reaction 2 of Preparation A, the compound of formula XIV is convertedto the corresponding nitro compound of formula XIII by reacting XIV withnitric acid in the presence of an acetic acid/acetic anhydride mixture.The reaction is stirred at a temperature between about 0° C. to about25° C., preferably about 10° C., for a time period between about 1 hoursto about 6 hours, preferably about 2 hours.

In reaction 3 of Preparation A, the nitro compound of formula XIII isconverted to the corresponding amino compound of formula XII by reducingXIII with ammonium formate in the presence of a catalyst, such aspalladium on carbon, and an ether/alcohol mixture. The reaction isstirred at a temperature between about 0° C. to about 75° C., preferablyabout 50° C., for a time period between about 1 hours to about 6 hours,preferably about 4 hours.

In reaction 1 of Preparation B, the diol compound of formula XV isconverted to the corresponding compound of formula XVIII by reacting XVwith a compound of the formula, Br—CHR²—CHR¹⁴—Cl, according to theprocedure described above in reaction 1 of Preparation A.

In reaction 2 of Preparation B, the compound of formula XVIII isconverted to the corresponding nitro compound of formula XVII accordingto the procedure described above in reaction 2 of Preparation A. inreaction 3 of Preparation B, the nitro compound of formula XVII isconverted to the corresponding amino compound of formula XVI accordingto the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation C, the diol compound of formula XV isconverted to the corresponding compound of formula XXI by reacting XVwith a compound of the formula, Br—CHR¹²—CI, according to the proceduredescribed above in reaction 1 of Preparation A.

In reaction 2 of Preparation C, the compound of formula XXI is convertedto the corresponding nitro compound of formula XX according to theprocedure described above in reaction 2 of Preparation A.

In reaction 3 of Preparation C, the nitro compound of formula XX isconverted to the corresponding amino compound of formula XIX accordingto the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation D, the compound of formula XXV is convertedto the corresponding compound of formula XXIV by reacting XXV withHCOONa. The reaction is stirred at a temperature between about 0° C. toabout 75° C., preferably about 50° C., for a time period between about 1hours to about 6 hours, preferably about 5 hours.

In reaction 2 of Preparation D, the compound of formula XXIV isconverted to the corresponding compound of formula XXIII according tothe procedure described above in reaction 1 of Preparation A.

In reaction 3 of Preparation D, the compound of formula XXIII isconverted to the corresponding compound of formula XXII according to theprocedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation E, the compound of formula XXV is convertedto the corresponding compound of formula XXIV according to the proceduredescribed above in reaction 1 of Preparation D.

In reaction 2 of Preparation E, the compound of formula XXIV isconverted to the corresponding compound of formula XXVII according tothe procedure described above in reaction 1 of Preparation B.

In reaction 3 of Preparation E, the nitro compound of formula XXVII isconverted to the corresponding amino compound of formula XXVI accordingto the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation F, the compound of formula XXV is convertedto the corresponding compound of formula XXIV according to the proceduredescribed above in reaction 1 of Preparation D.

In reaction 2 of Preparation F, the compound of formula XXIV isconverted to the corresponding compound of formula XXIX according to theprocedure described above in reaction 1 of Preparation C.

In reaction 3 of Preparation F, the compound of formula XXIX isconverted to the corresponding compound of formula XXVIII according tothe procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation G, the diamine compound of formula XXIX isconverted to the corresponding compound of formula XXX by reacting XXIXwith a compound of the formula, p-MePhSO₂Cl, in an anhydrous aminesolvent such as pyridine. The reaction was stirred at a temperaturebetween 25° C. to about 110° C., preferably about 100° C., for a timeperiod between about 2 hours to about 6 hours, preferably about 4 hours.

In reaction 2 of Preparation G, the compound of formula XXX is convertedto the corresponding compound of formula XXXI by reacting XXX with1,3-dibromopropane in the presence of n-butanol and sodium metal. Thereaction was stirred at a temperature between 0° C. to about 150° C.,preferably about 125° C., for a time period between about 8 hours toabout 30 hours, preferably about 24 hours.

In reaction 3 of Preparation G, the nitro compound of formula XVII isconverted to the corresponding amino compound of formula XVI accordingto the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation H, the diamine compound of formula XXIX isconverted to the corresponding compound of formula XXX by reacting XXIXwith a compound of the formula, pMePhSO₂Cl, in an anhydrous aminesolvent such as pyridine. The reaction was stirred at a temperaturebetween 25° C. to about 110° C., preferably about 100° C., for a timeperiod between about 2 hours to about 6 hours, preferably about 4 hours.

In reaction 2 of Preparation H, the compound of formula XXX is convertedto the corresponding compound of formula XXXII by reacting XXX with1,2-dibromoethane in the presence of n-butanol and sodium metal. Thereaction was stirred at a temperature between 0° C. to about 150° C.,preferably about 125° C., For a time period between about 8 hours toabout 30 hours, preferably about 24 hours.

In reaction 3 of Preparation H, the nitro compound of formula XXXII isconverted to the corresponding amino compound of formula XXXIV accordingto the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation 1, the diamine compound of formula XXIX isconverted to the corresponding compound of formula XXX by reacting XXIXwith a compound of the formula, NO₂PhSO₂Cl, in an anhydrous aminesolvent such as pyridine. The reaction was stirred at a temperaturebetween 25° C. to about 110° C., preferably about 100° C., for a timeperiod between about 2 hours to about 6 hours, preferably about 4 hours.

In reaction 2 of Preparation 1, the compound of formula XXX is convertedto the corresponding compound of formula XXXV by reacting XXX with ethyl1,1-dichloroacetate in the presence of n-butanol and sodium metal. Thereaction was stirred at a temperature between 0° C. to about 150° C.,preferably about 125° C., for a time period between about 8 hours toabout 30 hours, preferably about 24 hours.

In reaction 3 of Preparation 1, the nitro compound of formula XXXV isconverted to the corresponding amino compound of formula XXXVI accordingto the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation J, the diamine compound of formula XXIX isconverted to the corresponding compound of formula XXXVII by reactingXXIX with sodium formate in concentrated formic acid. The reaction wasstirred at a temperature between 25° C. to about 110° C., preferablyabout 100° C., for a time period between about 1 hours to about 4 hours,preferably about 2 hours.

In reaction 2 of Preparation J, the compound of formula XXVII isconverted to the corresponding compound of formula XXXIII by reactingXXXVII with neat thionyl chloride. The reaction was stirred at atemperature between 0° C. to about 65° C., preferably about 55° C., fora time period between about 2 hours to about 12 hours, preferably about8 hours.

In reaction 3 of Preparation J, the nitro compound of formula XXXVIII isconverted to the corresponding amino compound of formula XXXIX accordingto the procedure described above in reaction 3 of Preparation A.

In reaction 1 of Preparation K, the compound of formula XXXIX isconverted to the corresponding compound of formula XL according to theprocedure described in reaction 1 of Preparation A.

In reaction 1 of Preparation L, the compound of formula XLI is convertedto the corresponding compound of formula XLII according to the proceduredescribed in reaction 1 of Preparation A.

In reaction 1 of Preparation M, the compound of formula XLIII isconverted to the Corresponding compound of formula XLIV according to theprocedure described in reaction 1 of Preparation A.

In reaction 1 of Preparation N, the compound of formula XLV is convertedto the corresponding compound of formula XLVI according to the proceduredescribed in reaction 1 of Preparation A.

In reaction 1 of Preparation O, the compound of formula XLVII isconverted to the corresponding compound of formula XLVIII according tothe procedure described in reaction 1 of Preparation A.

In reaction 1 of Preparation P, the compound of formula XLIX isconverted to the corresponding compound of formula L according to theprocedure described in reaction 1 of Preparation A.

In reaction 1 of Scheme 1, the carboxylic acid compound of formula IV isconverted to the corresponding acid chloride compound of formula III byreacting IV with oxalyl chloride in a polar aprotic solvent, such asmethylene chloride. The reaction is stirred at a temperature betweenabout 0° C. to about 40° C., preferably about 25° C., for a time periodbetween about 2 hours to about 24 hours, preferably about 8 hours.

In reaction 2 of Scheme 1, the acid chloride compound of formula III isconverted to the corresponding compound of formula II by reacting IIIwith a compound of the formula

in the presence of a catalyst, such as pyridine, and a polar aproticsolvent such as dimethylformamide. The reaction is stirred at atemperature between about 0° C. to about 25° C., preferably about 5° C.,for a time period between about 1 hours to about 24 hours, preferablyabout 10 hours.

In reaction 1 of Scheme 2, the compound of formula VIIl is converted tothe corresponding carboxylic acid compound of formula VIl by treatingVIIl with N-chlorosuccimide followed by treatment with sodium hydroxide.The reaction is stirred at a temperature between about 0° C. to about25° C., preferably about 20° C., for a time period about 1 hours toabout 6 hours, preferably about 4 hours.

In reaction 2 of Scheme 2, the carboxylic acid compound of formula VIIis converted to the corresponding acid chloride compound of formula VIaccording to the procedure described above in reaction 1 of Scheme 1.

In reaction 3 of Scheme 2, the acid chloride of formula VI is convertedto the corresponding compound of formula V according to the proceduredescribed in reaction 2 of Scheme 1.

In reaction 1 of Scheme 3, the carboxylic acid compound of formula XI isconverted to the corresponding acid chloride compound of formula Xaccording to the procedure described above in reaction 1 of Scheme 1.

In reaction 2 of Scheme 3, the acid chloride compound of formula X isconverted to the corresponding compound of formula IX according to theprocedure described above in reaction 2 of Scheme 1.

A patient in need of glycogen phosphorylase inhibition is a patienthaving a disease or condition in which glycogen phosphorylase plays arole in the disease of condition. Examples of patients in need ofglycogen phoshphorylase inhibition include patients having diabetes(including Type I and Type II, impaired glucose tolerance, insulinresistance, and the diabetic complications, such a nephropathy,retinopathy, neuropathy and cataracts), hyperglycemia,hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia,atherosclerosis and tissue ischemia.

The characteristics of patients at risk of having atherosclerosis arewell known to those skilled in the art and include, patients who have afamily history of cardiovascular disease, including hypertension andatherosclerosis, obese patients, patient who exercise infrequently,patients with hypercholesterolemia, patients having high levels of lowdensity lipoprotein (LDL), patients having low levels of high densitylipoprotein (HDL), and the like.

Patients at risk of having myocardial ischemia and other tissueischemias are also well known to those skilled in the art and includepatients undergoing or having undergone surgery, trauma or great stress.

The compounds of the present invention are administered to a patient ina therapeutically effective amount. The compounds can be administeredalone or as part of a pharmaceutically acceptable composition orformulation. In addition, the compounds or compositions can beadministered all at once, as for example, by a bolus injection, multipletimes, such as by a series of tablets, or delivered substantiallyuniformly over a period of time, as for example, using transdermaldelivery. It is also noted that the dose of the compound can be variedover time.

In addition, the compounds of the present invention can be administeredalone, in combination with other compounds of the present invention, orwith other pharmaceutically active compounds. The other pharmaceuticallyactive compounds can be intended to treat the same disease or conditionas the compounds of the present invention or a different disease orcondition. If the patient is to receive or is receiving multiplepharmaceutically active compounds, the compounds can be administeredsimultaneously, or sequentially. For example, in the case of tablets,the active compounds may be found in one tablet or in separate tablets,which can be administered at once or sequentially in any order. Inaddition, it should be recognized that the compositions may be differentforms. For example, one or more compound may be delivered via a tablet,while another is administered via injection or orally as a syrup. Allcombinations, delivery methods and administration sequences arecontemplated.

Since one aspect of the present invention contemplates the treatment ofthe disease/conditions with a combination of pharmaceutically activeagents that may be administered separately, the invention furtherrelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof the present invention, and a second pharmaceutical compound. The kitcomprises a container for containing the separate compositions such as adivided bottle or a divided foil packet. Additional examples ofcontainers include syringes, boxes, bags, and the like. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a compound of the presentinvention can consist of one tablet or capsule, while a daily dose ofthe second compound can consist of several tablets or capsules and viceversa. The memory aid should reflect this and aid in correctadministration of the active agents.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of the present invention and other pharmaceutically activeagents, if desired, can be administered to a patient either orally,rectally, parenterally, (for example, intravenously, intramuscularly, orsubcutaneously) intracisternally, intravaginally, intraperitoneally,intravesically, locally (for example, powders, ointments or drops), oras a buccal or nasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Microorganism contaminationcan be prevented by adding various antibacterial and antifungal agents,for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.It may also be desirable to include isotonic agents, for example,sugars, sodium chloride, and the like. Prolonged absorption ofinjectable pharmaceutical compositions can be brought about by the useof agents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules tablets,powders, and granules. In such solid dosage forms, the active compoundis admixed with at least one inert customary excipient (or carrier) suchas sodium citrate or dicalcium phosphate or (a) fillers or extenders, asfor example, starches, lactose, sucrose, mannitol, and silicic acid; (b)binders, as for example, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as forexample, glycerol; (d) disintegrating agents, as for example, agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certaincomplex silicates, and sodium carbonate; (e) solution retarders, as forexample, paraffin; (f) absorption accelerators, as for example,quaternary ammonium compounds; (g) wetting agents, as for example, cetylalcohol and glycerol monostearate; (h) adsorbents, as for example,kaolin and bentonite; and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, and tablets, thedosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be used as fillers in softand hard filled gelatin capsules using such excipients as lactose ormilk sugar, as well as high molecular weight polyethylene glycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may also containopacifying agents, and can also be of such composition that they releasethe active compound or compounds in a certain part of the intestinaltract in a delayed manner. Examples of embedding compositions that canbe used are polymeric substances and waxes. The active compounds canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage form may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylAlcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and seasame seed oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compound, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administration are preferable suppositories,which can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax, which are solid atordinary room temperature, but liquid at body temperature, andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

Dosage forms for topical administration of a compound of the presentinvention include ointments, powders, sprays and inhalants. The activecompound or compounds are admixed under sterile condition with aphysiologically acceptable carrier, and any preservatives, buffers, orpropellants that may be required. Opthalmic formulations, eye ointments,powders, and solutions are also contemplated as being within the scopeof this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 3,000 mg per day.For a normal adult human having a body weight of about 70 kg, a dosagein the range of about 0.01 to about 100 mg per kilogram body weight istypically sufficient. The specific dosage and dosage range that can beused depends on a number of factors, including the requirements of thepatient, the severity of the condition or disease being treated, and thepharmacological activity of the compound being administered. Thedetermination of dosage ranges and optimal dosages for a particularpatient is well within the ordinary skill in the art.

The following paragraphs describe exemplary formulations, dosages etc.useful for non-human animals. The administration of a compound of thepresent invention can be effected orally or non-orally, for example byinjection. An amount of a compound of the present invention isadministered such that an effective dose is received, generally adaily-dose which, when administered orally to an animal is usuallybetween 0.01 and 100 mg/kg of body weight, preferably between 0.1 and 50mg/kg of body weight. Conveniently, the medication can be carried in thedrinking water so that a therapeutic dosage of the agent is ingestedwith the daily water supply. The agent can be directly metered intodrinking water, preferably in the form of a liquid, water-solubleconcentrate (such as an aqueous solution of a water soluble salt).Conveniently, the active ingredient can also be added directly to thefeed, as such, or in the form of an animal feed supplement, alsoreferred to as a premix or concentrate. A premix or concentrate oftherapeutic agent in a carrier is more commonly employed for theinclusion of the agent in the feed. Suitable carriers are liquid orsolid, as desired, such as water, various meals such as alfalfa meal,soybean meal, cottonseed oil meal, linseed oil meal, corncob meal andcorn meal, molasses, urea, bone meal, and mineral mixes such as arecommonly employed in poultry feeds. A particularly effective carrier isthe respective animal feed itself; that is, a small portion of suchfeed. The carrier facilitates uniform distribution of the activematerials in the finished feed with which the premix is blended. It isimportant that the compound be thoroughly blended into the premix and,subsequently, the feed. In this respect, the agent may be dispersed ordissolved in a suitable oily vehicle such as soybean oil, corn oil,cottonseed oil, and the like, or in a volatile organic solvent and thenblended with the carrier. It will be appreciated that the proportions ofactive material in the concentrate are capable of wide variation sincethe amount of agent in the finished feed may be adjusted by blending theappropriate proportion of premix with the feed to obtain a desired levelof therapeutic agent.

High potency concentrates may be blended by the feed manufacturer withproteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet.

Alternatively, such concentrated supplements may be added directly tothe feed to produce a nutritionally balanced, finished feed containing atherapeutically effective level of a compound according to theinvention. The mixtures are thoroughly blended by standard procedures,such as in a twin shell blender, to ensure homogeneity.

If the supplement is used as a top dressing for the feed, it likewisehelps to ensure uniformity of distribution of the active material acrossthe top of the dressed feed.

Drinking water and feed effective for increasing lean meat depositionand for improving lean meat to fat ratio are generally prepared bymixing a compound of the invention with a sufficient amount of animalfeed to provide from about 10⁻³ to about 500 ppm of the compound in thefeed or water.

The preferred medicated swine, cattle, sheep and goat feed generallycontain from about 1 to about 400 grams of active ingredient per ton offeed, the optimum amount for these animals usually being about 50 toabout 300 grams per ton of feed.

The preferred poultry and domestic pet feeds usually contain about 1 toabout 400 grams and preferably about 10 to about 400 grams of activeingredient per ton of feed.

For parenteral administration in animals, the compounds of the presentinvention may be prepared in the form of a paste or a pellet andadministered as an implant, usually under the skin of the head or ear ofthe animal.

In general, parenteral administration involves injection of a sufficientamount of a compound of the present invention to provide the animal withabout 0.01 to about 100 mg/kg/day of body weight of the activeingredient. The preferred dosage for poultry, swine, cattle, sheep,goats and domestic pets is in the range of from about 0.1 to about 50mg/kg/day.

Paste formulations can be prepared by dispersing the active compound ina pharmaceutically acceptable oil such as peanut oil, sesame oil, cornoil or the like.

Pellets containing an effective amount of a compound of the presentinvention can be prepared by admixing a compound of the presentinvention with a diluent such as carbowax, carnuba wax, and the like,and a lubricant, such as magnesium or calcium stearate, can be added toimprove the pelleting process.

It is, of course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level. Moreover,it has been found that implants may also be made periodically during theanimal treatment period in order to maintain the proper active agent inthe level animal's body.

The term “salts” refers to inorganic and organic salts of compounds ofthe present invention. The salts can be prepared in situ during thefinal isolation and purification of a compound, or by separatelyreacting a purified compound in its free base form with a suitableorganic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. The salts mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and, the like. See, for example, S. M. Berge, et al., “PharmaceuticalSalts,” J Pharm. Sci, 66: 1-19 (1977).

The term “prodrug” means compounds that are transformed in vivo to yielda compound of Formula I. The transformation may occur by variousmechanisms, such as through hydrolysis in blood. A discussion of the useof prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as NovelDelivery Systems;” Vol. 14 of the A.C.S.

Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

It is also intended that the invention disclosed herein encompasscompounds that are synthesized in vitro using laboratory techniques,such as those well known to synthetic chemists; or synthesized using invivo techniques, such as through metabolism, fermentation, digestion,and the like. It is also contemplated that the compounds of the presentinvention may be synthesized using a combination of in vitro and in vivotechniques.

The present invention also includes isotopically-labelled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of this invention. Certainisotopically-labelled compounds of the p resent invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detection.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.isotopically labelled compounds of Formula I of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples below, bysubstituting a readily available isotopically labelled reagent for anon-isotopically labelled reagent.

In general the compounds of this invention can be made by processeswhich include processes analogous to those known in the chemical arts,particularly in light of the description contained herein.

In another aspect, the present invention concerns the treatment ofdiabetes, including impaired glucose tolerance, insulin resistance,insulin dependent diabetes mellitus (Type I) and non-insulin dependentdiabetes mellitus (NIDDM or Type II). Also included in the treatment ofdiabetes are the treatment of the diabetic complications, such asneuropathy, nephropathy, retinopathy or cataracts.

Diabetes can be treated by administering to a patient having diabetes(Type I or Type II), insulin resistance, impaired glucose tolerance, orany of the diabetic complications such as neuropathy, nephropathy,retinopathy or cataracts, a therapeutically effective amount of acompound of the present invention. It is also contemplated that diabetesbe treated by administering a compound of the present invention or another glycogen phosphorylase inhibitor in combination with an additionalagent that can be used to treat diabetes and/or obesity. Preferredgylcogen phosphorylase inhibitors that are useful in combination withother agents useful to treat diabetes and/or obesity include those ofFormula I. Additional preferred gylcogen phosphorylase inhibitors aredisclosed in PCT publications WO 96/39384 and WO 96/39385.

Representative agents that can be used to treat diabetes include insulinand insulin analogs: (e.g., LysPro insulin. inhaled formulationscomprising insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH₂;sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide,tolazamide, acetohexamide, glypizide, glimepiride, repaglinide,meglitinide; biguanides: metformin, phenformin, buformin; α2-antagonistsand imidazolines: midaglizole, isaglidole, deriglidole, idazoxan,efaroxan. fluparoxan; other insulin secretagogues: linogliride,insulinotropin, exendin-4, BTS-67582, A-4166; giitazones: ciglitazone,pioglitazone, englitazone. troglitazore, darglitazone, rosiglitazone;PPAR-gamma agonists; RXR agonists: JTT-501, MCC -555, MX-6054,DRF2593,GI-262570, KRP-297, LG100268; fatty acid oxidation inhibitors:clomoxir, etomoxir; α-glucosidase inhibitors: precose, acarbose,miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945;β-agonists: BRL 35135, BRL 37344, Ro 16-8714. ICI D7114, CL 316,243,TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type:sildenafil, L686398: L-386,398; lipid-lowering agents: benfluorex,atorvastatin; antiobesity agents: fenfluramine, orlistat, sibutramine;vanadate and vanadium complexes (e.g., Naglivan®) and peroxovanadiumcomplexes; amylin antagonists: pramlintide, AC-137; lipoxygenaseinhibitors: masoprocal; somatostatin analogs: BM-23014, seglitide,octreotide; glucagon antagonists: BAY 276-9955; insulin signalingagonists, insulin mimetics, PTP1B inhibitors: L-783281, TER17411,TER17529; gluconeogenesis inhibitors:GP3034; somatostatin analogs andantagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994;glucose transport stimulating agents: BM-130795; glucose synthase kinaseinhibitors: lithium chloride, CT98014, CT98023; galanin receptoragonisnts; MTP inhibitors such as those disclosed in U.S. provisionalpatent application No. 60/164,803; growth hormone secretagogues such asthose disclosed in PCT publication numbers WO 97/24369 and WO 98/58947;NPY antagonists: PD-160170, BW-383, BW1229, CGP-71683A, NGD 95-1,L-152804; Anorectic agents including 5-HT and 5-HT2C receptorantagonists and/or mimetics: dexfenfluramine, Prozac®, Zoloft®; CCKreceptor agonists: SR-27897B; galanin receptor antagonists; MCR-4antagonists: HP-228; leptin or mimetics:leptin; 11-beta-hydroxysteroiddehydrogenase type-Iinhibitors; urocortin mimetics, CRF antagonists, andCRF binding proteins:

RU-486, urocortin. Other anti-diabetic agents that can be used incombination with a glycogen phosphorylase inhibitor include ergoset andD-chiroinositol. Any combination of agents can be administered asdescribed above.

In addition to the categories and compounds mentioned above, gylcogenphosphorylase inhibitors, preferrably the compounds of the presentinvention, can be administered in combination with thyromimeticcompounds, aldose reductase Inhibitors, glucocorticoid receptorantagonists, NHE-1 inhibitors, or sorbitol dehydrogenase inhibitors, orcombinations thereof, to treat or prevent diabetes, insulin resistance,diabetic neuropathy, diabetic nephropathy, diabetic retinopathy,cataracts, hyperglycemia, hypercholesterolemia, hypertension,hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia,particularly myocardial ischemia.

It is generally accepted that thyroid hormones, specifically,biologically active iodothyronines, are critical to normal developmentand to maintaining metabolic homeostasis. Thyroid hormones stimulate themetabolism of cholesterol to bile acids and enhance the lipolyticresponses of fat cells to other hormones. U.S. Pat. Nos. 4,766,121;4,826,876; 4,910,305; and 5,061,798 disclose certain thyroid hormonemimetics (thyromimetics), namely,3,5-dibromo-3-[6-oxo-3(1H)-pyridazinylmethyl]-thyronines. U.S. Pat. No.5,284,971 discloses certain thyromimetic cholesterol lowering agents,namely, 4-(3-cyclohexyl-4-hydroxy or -methoxy phenylsulfonyl)-3,5dibromo-phenylacetic compounds. U.S. Pat. No. 5,401,772; 5,654,468; and5,569,674 disclose certain thyromimetics that are lipid lowering agents,namely, heteroacetic acid derivatives. In addition, certain oxamic acidderivatives of thyroid hormones are known in the art. For example, N.Yokoyama, et al. in an article published in the Journal of MedicinalChemistry, 38 (4): 695-707 (1995) describe replacing a —CH₂ group in anaturally occurring metabolite of T₃ with an —NH group resulting in—HNCOCO₂H. Likewise, R. E. Steele et al. in an article published inInternational Congressional Service (Atherosclerosis X) 1066: 321-324(1995) and Z. F. Stephan et al. in an article published inAtherosclerosis, 126: 53-63 (1996), describe certain oxamic acidderivatives useful as lipid-lowering thyromimetic agents, yet devoid ofundesirable cardiac activities. Other useful thyromimetics that can beused in combination with a glycogen phosphorylase inhibitor includeCGS-26214.

Each of the thyromimetic compounds referenced above and otherthyromimetic compounds can be used in combination with the compounds ofthe present invention to treat or prevent diabetes, insulin resistance,diabetic neuropathy, diabetic nephropathy, diabetic retinopathy,cataracts hyperglycemia, hypercholesterolemia, hypertension,hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.

The compounds of the present invention can also be used in combinationwith aldose reductase inhibitors. Aldose reductase inhibitors constitutea class of compounds that have become widely known for their utility inpreventing and treating conditions arising from complications ofdiabetes, such as diabetic neuropathy and nephropathy. Such compoundsare well known to those skilled in the art and are readily identified bystandard biological tests. For example, the aldose reductase inhibitorszopolrestat, 1-phthalazineacetic acid,3,4-dihydro-4-oxo-S-[[5-(trifuoromethyl)-2-benzothiazoly]methyl]-, andrelated compounds are described in U.S. Pat. No. 4,939,140 to Larson etal.

Aldose reductase inhibitors have been taught for use in lowering lipidlevels. in mammals. See, for example, U.S. Pat. No. 4,492,706 toKallai-sanfacon and EP 0 310 931 A2 (Ethyl Corporation).

U.S. Pat. No. 5,064,830 to Going discloses the use of certainoxophthalazinyl acetic acid aldose reductase inhibitors, includingzopolrestat, for lowering of blood uric acid levels.

Commonly assigned U.S. Pat. No. 5,391,551 discloses the use of certainaldose reductase inhibitors, including zopolrestat, for lowering bloodlipid levels in humans. The disclosure teaches that therapeuticutilities derive from the treatment of diseases caused by an increasedlevel of triglycerides in the blood, such diseases includecardiovascular disorders such as thrombosis, arteriosclerosis,myocardial infarction, and angina pectoris. A preferred aldose reductaseinhibitor is 1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-, alsoknown as zopolrestat.

The term aldose reductase inhibitor refers to compounds that inhibit thebioconversion of glucose to sorbitol, which is catalyzed by the enzymealdose reductase.

Any aldose reductase inhibitor may be used in a combination with acompound of the present invention. Aldose reductase inhibition isreadily determined by those skilled in the art according to standardassays (J. Malone, Diabetes, 29:861-864 (1980). “Red Cell Sorbitol, anIndicator of Diabetic Control”). A variety of aldose reductaseinhibitors are described herein; however, other aldose reductaseinhibitors useful in the compositions and methods of this invention willbe known to those skilled in the art.

The activity of an aldose reductase inhibitor in a tissue can bedetermined by testing the amount of aldose reductase inhibitor that isrequired to lower tissue sorbitol (i.e., by inhibiting the furtherproduction of sorbitol consequent to blocking aldose reductase) or lowertissue fructose (by inhibiting the production of sorbitol consequent toblocking aldose reductase and consequently the production of fructose.

Accordingly, examples of aldose reductase inhibitors useful in thecompositions, combinations and methods of the present invention include:

1. 3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-1-phthalazineacetic acid(ponalrestat, U.S. Pat. No. 4,251,528);

2.N[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl]-N-methylglycine(tolrestat, U.S. Pat. No. 4,600,724);

3. 5-[(Z,E)-β-methylcinnamylidene]-4-oxo-2-thioxo-3-thiazolideneaceticacid (epalrestat, U.S. Pat. No. 4,464,382, U.S. Pat. No. 4,791,126, U.S.Pat. No. 4,831,045);

4. 3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid (zenarestat, U.S. Pat. Nos. 4,734,419, and4,883,800);

5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Pat.No. 4,883,410);

6. 2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid(U.S. Pat. No. 4,883,410);

7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid(U.S. Pat. No. 4,771,050);

8.3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2H-1,4-benzothiazine-2-aceticacid (SPR-210, U.S. Pat. No. 5,252,572);

9.N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methyl-benzeneacetamide(ZD5522, U.S. Pat. No. 5,270,342 and U.S. Pat. No. 5,430,060);

10. (S)-6-fluorospiro[chroman-4,4′-imidazolidine]-2,5′-dione (sorbinil.U.S. Pat. No. 4,130,714);

11.d-2-methyl-6-fluoro-spiro(chroman-4′,4′-imidazolidine)-2′,5′-dione,(U.S.Pat. No. 4,540,704);

12. 2-fluoro-spiro(9H-fluorene-9,4′-imidazolidine)2′,5′-dione (U.S. Pat.No. 4,438,272);

13. 2,7-di-fluoro-spiro(9H-fluorene-9,4′-imidazolidine)2′,5′-dione (U.S.Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);

14.2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4′-imidazolidine)2′,5′-dione(U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);

15. 7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3′-pyrrolidine)2,5′-dione(U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);

16.d-cis-6′-chloro-2′,3′-dihydro-2′-methyl-spiro-(imidazolidine-4,4′-4′-H-pyrano(2,3-b)pyridine)-2,5-dione(U.S. Pat. No. 4,980,357);

17.spiro[imidazolidine-4,5′(6H)-quinoline]2,5-dione-3′-chloro-7,′8′-dihydro-7′-methyl-(5′-cis)(U.S.Pat. No. 5,066,659);

18.(2S,4S)-6-fluoro-2′,5′-dioxospiro(chroman-4,4′-imidazolidine)-2-carboxamide(U.S. Pat. No. 5,447,946); and

19.2-[(4-bromo-2-fluorophenyl)methyl]-6-flourospiro[isoquinoline-4(1H),3′-pyrrolidine]-1,2′,3,5′(2H)-tetrone(ARI-509, U.S. Pat. No. 5,037,831).

Other aldose reductase inhibitors include compounds having formula labelow

or a pharmaceutically acceptable salt or prodrug thereof, wherein

Z is O or S;

R¹ is hydroxy or a group capable of being removed in vivo to produce acompound of formula I wherein R¹ is OH; and

X and Y are the same or different and are selected from hydrogen,trifluoromethyl, fluoro, and chloro.

A preferred subgroup within the above group of aldose reductaseinhibitors includes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17,and the following compounds of Formula Ia:

20.3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)-4-oxophthalazin-1-yl-aceticacid [R¹=hydroxy; X═F; Y═H];

21.3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X═Y═F];

22. 3- (5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin1-ylacetic acid [R¹=hydroxy; X═Cl; Y═H];

23.3-(5,7-dichlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X═Y═Cl]:

24.3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-ylaceticacid [R¹=hydroxy; X═CF₃; Y═H];

25.3,4-dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)-4-oxophthalazin-1-yl-aceticacid [R¹=hydroxy; X═F; Y═H];

26.3-(5,7-difluorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X═Y═F];

27.3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X═Cl: Y═H];

28.3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X═Y═Cl]; and

29. zopolrestat; 1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-[R¹=hydroxy;X═trifluoromethyl; Y═H].

In compounds 20-23, and 29 Z is S. In compounds 24-28, Z is O.

Of the above subgroup, compounds 20-29 are more preferred with 29especially preferred. Procedures for making the aldose reducataseinhibitors of formula Ia can be found in PCT publication number WO99/26659.

Each of the aldose reductase inhibitors referenced above and otheraldose reductase inhibitors can be used in combination with thecompounds of the present invention to treat diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, cataracts, hyperglycemia, hypercholesterolemia,hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, ortissue ischemia.

The compounds of the present invention can also be used in combinationwith glucocorticoid receptor antagonists. The glucocorticoid receptor(GR) is present in glucocorticoid responsive cells where it resides inthe cytosol in an inactive state until it is stimulated by an agonist.Upon stimulation the glucocorticoid receptor translocates to the cellnucleus where it specifically interacts with DNA and/or protein(s) andregulates transcription in a glucocorticoid responsive manner. Twoexamples of proteins that interact with the glucocorticoid receptor arethe transcription factors, API and NFκ-B. Such interactions result ininhibition of API- and NFκ-B- mediated transcription and are believed tobe responsible for the anti-inflammatory activity of endogenouslyadministered glucocorticoids. In addition, glucocorticoids may alsoexert physiologic effects independent of nuclear transcription.Biologically relevant glucocorticoid receptor agonists include cortisoland corticosterone. Many synthetic glucocorticoid receptor agonistsexist including dexamethasone, prednisone and prednisilone. Bydefinition, glucocorticoid receptor antagonists bind to the receptor andprevent glucocorticoid receptor agonists from binding and eliciting GRmediated events, including transcription. RU486 is an example of anon-selective glucocorticoid receptor antagonist. GR antagonists can beused in the treatment of diseases associated with an excess or adeficiency of glucocorticoids in the body. As such, they may be used totreat the following: obesity, diabetes, cardiovascular disease.,hypertension, Syndrome X, depression, anxiety, glaucoma, humanimmunodeficiency virus (HIV) or acquired immunodeficiency syndrome(AIDS), neurodegeneration (for example, Alzheimer's and Parkinson's),cognition enhancement, Cushing's Syndrome, Addison's Disease,osteoporosis, frailty, inflammatory diseases (such as osteoarthritis,rheumatoid arthritis, asthma and rhinitis), tests of adrenal function,viral infection, immunodeficiency, immunomodulation, autoimmunediseases, allergies, wound healing, compulsive behavior, multi-drugresistance, addiction, psychosis, anorexia, cachexia, post-traumaticstress syndrome, post-surgical bone fracture, medical catabolism andprevention of muscle frailty. Examples or GR antagonists that can beused in combination with a compound of the present invention includecompounds of formula lb below:

an isomer thereof, a prodrug of said compound or isomer, or apharmaceutically acceptable salt of said compound, isomer or prodrug;wherein m is 1 or 2;

—represents an optional bond;

A is selected from the group consisting of

A-5

D is CR₇, CR₇R₁₆, N, NR₇ or O;

E is C, CR₆ or N;

F is CR₄, CR₄R₅ or O;

G, H and I together with 2 carbon atoms from the A-ring or 2 carbonatoms from the B-ring form a 5-membered heterocyclic ring comprising oneor more N, O or atoms; provided that there is at most one of O and S perring; J, K, L and M together with 2 carbon atoms from the B-ring forms a6-membered heterocyclic ring comprising 1 or more N atoms;

X is a) absent, b) —CH₂—, c) —CH(OH)— or d) —C(O)—;

R₁ is a) —H, b) -Z-CF₃, c) —(C₁-C₆)alkyl, d) —(C₂-C₆)alkenyl, e)—(C₂-C₆)alkynyl, f) —CHO, g) —CH═N—OR₁₂, h) -Z-C(O)OR₁₂, i)-Z-C(O)—NR₁₂R₁₃, j) -Z-C(O)—NR₁₂-Z-het, k) -Z-NR₁₂R₁₃, l) -Z-NR₁₂het, m)-Z-het, n) -Z-O-het, o) -Z-aryl′, p) -Z-O-aryl′, q) —CHOH-aryl′ or r)—C(O)-aryl′ wherein aryl′ in substituents o) to r) is substitutedindependently with 0, 1 or 2 of the following: -Z-OH, -Z-NR₁₂R₁₃,-Z-NR₁₂-het, —C(O)NR₁₂R₁₃, —C(O)O(C₁-C₆)alkyl, —C(O)OH, —C(O)-het,—NR₁₂—C(O)—(C₁-C₆)alkyl, —NR₁₂—C(O)—(C₂-C₆)alkenyl,—NR₁₂—C(O)—(C₂-C₆)alkynyl, —NR₁₂—C(O)-Z-het, —CN, -Z-het,—O—(C₁-C₃)alkyl-C(O)—NR₁₂Rl₃, —O—(C₁-C₃)alkyl-C(O)O(C₁-C₆)alkyl,—NR₁₂-Z-C(O)O(C_(1-C) ₆)alkyl, —N(Z-C(O)O(C₁-C₆)alkyl)₂,—NR₁₂-Z-C(O)—NR₁₂R₁₃, -Z-NR₁₂—SO₂—R¹³, —NR₂—SO₂-het, —C(O)H,-Z-NR₁₂-Z-O(C₁-C₆)alkyl, -Z-NR₁₂-Z-NR₁₂R₁₃, -Z-NR₁₂—(C₃-C₆)cycloalkyl,-Z-N(Z-O(C₁-C₆)alkyl)₂, —SO₂R₁₂, —SOR₁₂, —SR₁₂, —SO₂NR₁₂R₁₃,—O—C(O)—(C₁-C₄)alkyl, —O—SO₂—(C₁-C₄)alkyl, -halo or —CF₃;

Z for each occurrence is independently a) -(CO-C₆)alkyl, b)-(C₂-C,)alkenyl or c) —(C₂-C₆)alkynyl;

R₂ is a) —H, b) -halo, c) —OH, d) —(C₁-C₆)alkyl substituted with 0 or1-OH, e) —NR₁₂R₁₃, f) -Z-C(O)O(C₁-C₆)alkyl, g) -Z-C(O)NR₁₂R₃, h)—O—(C₁-C₆)alkyl, i) -Z-O—C(O)—(C₁-C₆)alkyl, j)-Z-O-(C₁-C₃)alkyl-C(O)—NR₁₂R₁₃, k) -Z-O—(C₁-C₃)alkyl-C(O)—O(C₁-C₆)alkyl,l) —O—(C₂-C₆)alkenyl, m) —O—(C₂-C₆)alkynyl n) —O-Z-het, o) —COOH, p)—C(OH)R₁₂R₁₃ or q) -Z-CN;

R₃ is a) —H, b) —(C₁-C₁₀)alkyl wherein 1 or 2 carbon atoms, other thanthe connecting carbon atom, may optionally be replaced with 1 or 2heteroatoms independently selected from S, O and N and wherein eachcarbon atom is substituted with 0, 1 or 2 R_(y), c) —(C₂-C₁₀)alkenylsubstituted with 0, 1 or 2 R_(y), d) —(C₂-C₁₀)alkynyl wherein 1 carbonatom, other than the connecting carbon atom, may optionally be replacedwith 1 oxygen atom and wherein each carbon atom is substituted with 0, 1or 2 R_(y), e) —CH═C═CH₂, f) —CN, g) —(C₃-C₆)cycloalkyl, h) -Z-aryl, i)-Z-het, j) —C(O)O(C_(1-C) ₆)alkyl, k) —O(C₁-C₆)alkyl, l) -Z-S—R₁₂, m)-Z-S(O)—R₁₂, n) -Z-S(O)₂—R₁₂, o) —CF₃ p) —NR₁₂O—(C₁-C₆)alkyl or q)—CH₂OR_(y);

provided that one of R₂ and R₃ is absent when there is a double bondbetween CR₂R₃ (the 7 position) and the F moiety (the 8 position) of theC-ring;

R_(y) for each occurrence is independently a) —OH, b) -halo, c) -Z-CF₃,d) -Z-CF(C_(-C) ₃ alkyl)₂, e) —CN, f) —NR₁₂R₁₃, g) —(C₃-C₆)cycloalkyl,h) —(C₃-C₆)cycloalkenyl, i) —(C₀-C₃)alkyl-aryl, j) -het or k) —N₃;

or R₂ and R₃ are taken together to form a) ═CHR₁₁, b) ═NOR₁₁, c) ═O, d)═N—NR₁₂, e) ═N—NR₁₂—C(O)—R₁₂, f) oxiranyl or g) 1,3-dioxolan-4-yl;

R₄ and R₅ for each occurrence are independently a) —H, b) —CN, c)—(C₁-C₆)alkyl substituted with 0 to 3 halo, d) —(C₂-C₆)alkenylsubstituted with 0 to 3 halo, e) —(C₂-C₆)alkynyl substituted with 0 to 3halo, f) —O—(C₁-C₆)alkyl substituted with 0 to 3 halo, g)—O—(C₂-C₆)alkenyl substituted with 0 to 3 halo, h) —O—(C₂-C₆)alkynylsubstituted with 0 to 3 halo, i) halo, j) —OH, k) (C₃-C₆)cycloalkylor 1) (C₃-C₆)cycloalkenyl;

or R₄ and R₅ are taken together to form ═O;

R₆ is a) —H, b) —CN, c) —(C₁-C₆)alkyl substituted with 0 to 3 halo, d)—(C₂-C₆)alkenyl substituted with 0 to 3 halo, e) —(C₂-C₆)alkynylsubstituted with 0 to 3 halo or f) —OH;

R₇ and R₁₆ for each occurrence are independently a) —H, b) -halo, c)—CN, d) —(C₁-C₆)alkyl substituted with 0 to 3 halo, e) —(C₂-C₆)alkenylsubstituted with 0 to 3 halo or f) —(C₂-C₆)alkynyl substituted with 0 to3 halo; provided that R₇ is other than —CN or -halo when D is NR₇;

or R₇ and R₁₆ are taken together to form ═O;

R₈, R₉, R₁₄ and R₁₅ for each occurrence are independently a) —H, b)-halo, c) (C₁-C₆)alkyl substituted with 0 to 3 halo, d) —(C₂-C₆)alkenylsubstituted with 0 to 3 halo, e) —(C₂-C₆)alkynyl substituted with 0 to 3halo, f) —CN, g) —(C₃-C₆)cycloalkyl, h) —(C₃-C₆)cycloalkenyl, i) —OH, j)—O—(C₁-C₆)alkyl, k) —O—(C₁-C₆)alkenyl, l) —O—(C₁-C₆)alkynyl, m)—NR₁₂R₁₃, n) —C(O)OR₁₂ or o) —C(O)NR₁₂R₁₃;

or R₈ and R₉ are taken together on the C-ring to form ═O; provided thatwhen m is 2, only one set of R₈ and R₉ are taken together to form ═O;

or R₁₄ and R₁₅ are taken together to form ═O; provided that when R₁₄ andR₁₅ are taken together to form ═O, D is other than CR₇ and E is otherthan C;

R₁₀ is a) —(C₁-C₁₀)alkyl substituted with 0 to 3 substituentsindependently selected from -halo, —OH and —N₃, b) —(C₂-C₁₀)alkenylsubstituted with 0 to 3 substituents independently selected from -halo,—OH and —N₃, c) —(C₂-C₁₀)alkynyl substituted with 0 to 3 substituentsindependently selected from -halo, —OH and —N₃, d) -halo, e) -Z-CN, f)—OH, g) -Z-het, h) -Z-NR₁₂R₁₃, i) -Z-C(O)-het, j) -Z-C(O)—(C₁-C₆)alkyl,k) -Z-C(O)—NR₁₂R₁₃, l) -Z-C(O)—NR₁₂-Z-CN, m) -Z-C(O)—NR₁₂-Z-het, n)-Z-C(O)—NR₁₂-Z-aryl, o) -Z-C(O)—NR₁₂-Z-NR₁₂R₁₃, p)-Z-C(O)-NR₁₂-Z-O(C₁-C₆)alkyl, q) —(C₁-C₆)alkyl-C(O)OH, r)-Z-C(O)O(C₁-C₆)alkyl, s) -Z-O—(C₀-C₆)alkyl-het, t)-Z-O—(C₁-C₆)alkyl-aryl, u) -Z-O—(C₁-C₆)alkyl substituted with 0 to 2R_(x), v) -Z-O—(C₁-C₆)alkyl-CH(O), w) -Z-O—(C₁-C₆)alkyl-NR₁₂-het, x)-Z-O-Z-het-Z-het, y) -Z-O-Z-het-Z-NR₁₂R₁₃, z) -Z-O-Z-het-C(O)-het, a1)-Z-O-Z-C(O)-het, b1) -Z-O-Z-C(O)-het-het, c1) -Z-O-Z-C(O)—(C₁-C₆)alkyl,d1) -Z-O-Z-C(S)-NR₁₂R₁₃, e1) -Z-O-Z-C(O)—NR₁₂R₁₃, f1)-Z-O-Z-(C₁-C₃)alkyl-C(O)—NR₁₂R₁₃, g1) -Z-O-Z-C(O)—O(C₁-C₆)alkyl, h1)-Z-O-Z-C(O)—OH, i1) -Z-O-Z-C(O)—NR₁₂—O(C₁-C₆)alkyl, j1)-Z-O-Z-C(O)—NR₁₂—OH, k1) -Z-O-Z-C(O)—NR₁₂-Z-NR₁₂R₁₃, l1)-Z-O-Z-C(O)—NR₁₂-Z-het, m1) -Z-(O-Z-C(O)-NR₁₂—SO₂—(C₁-C₆)alkyl, n1)-Z-O-Z-C(═NR₂₂)(NR₁₂R₁₃), o1) -Z-O-Z-C(═NOR₁₂)(NR₁₂R₁₃), p1)-Z-NR₁₂—C(O)—O-Z-NR₁₂R₁₃, q1) -Z-S—C(O)—NR, r1) -Z-O—SO₂—(C₁-C₆)alkyl,s1) -Z-O—SO₂-aryl, t1) -Z-O-SO₂—NR₁₂R₁₃, u1) -Z-O-SO₂—CF₃, v1)-Z-NR₁₂C(O)OR₁₃ or w1) -Z-NR₁₂C(O)R₁₃;

or R₉ and R₁₀ are taken together on the moiety of formula A-5 to form a)═O or b) ═NOR₁₂;

R₁₁ is a) —H, b) —(C₁-C₅)alkyl, c) —(C₃-C₆)cycloalkyl or d)—(C₀-C₃)alkyl-aryl;

R₁₂ and R₁₃for each occurrence are each independently a) —H, b)—(C₁-C₆)alkyl wherein 1 or 2 carbon atoms, other than the connectingcarbon atom, may optionally be replaced with 1 or 2 heteroatomsindependently selected from S, O and N and wherein each carbon atom issubstituted with 0 to 6 halo, c) —(C₂-C₆)alkenyl substituted with 0 to 6halo or d) —(C₁-C₆)alkynyl wherein 1 carbon atom, other than theconnecting carbon atom, may optionally be replaced with 1 oxygen atomand wherein each carbon atom is substituted with 0 to 6 halo;

or R₁₂ and R₁₃ are taken together with N to form het;

or R₆ and R₁₄ or R₁₅ are taken together to form 1,3-dioxolanyl;

aryl is a) phenyl substituted with 0 to 3 R_(x), b) naphthyl substitutedwith 0 to 3 R_(x) or c) biphenyl substituted with 0 to 3 R_(x);

het is a 5-, 6- or 7-membered saturated, partially saturated orunsaturated ring containing from one (1) to three (3) heteroatomsindependently selected from the group consisting of nitrogen, oxygen andsulfur; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another heterocycle;and the nitrogen may be in the oxidized state giving the N-oxide form;and substituted with 0 to 3 R_(x);

R_(x) for each occurrence is independently a) -halo, b) —OH, c)—(C₁-C₆)alkyl, d) —(C₂-C₆)alkenyl, e) —(C₂-C₆)alkynyl, f)—O(C₁-C₆)alkyl, g) —O(C₂-C₆)alkenyl, h) —O(C₂-C₆)alkynyl, i)—(CO-C₆)alkyl-NR₁₂R₁₃, j) —C(O)—NR₁₂R₁₃, k) -Z-SOR₁₂l) -Z-SOR₁₂, m)-Z-SR₁₂, n) —NR₁₂—SO₂R₁₃, o) —NR₁₂—C(O)—R₁₃, p) —NR₁₂—OR₁₃, q)—SO₂—NR₁₂R₁₃, r) —CN, s) —CF₃, t) —C(O)(C₁-C₆)alkyl, u) ═O, v)-Z-SO₂-phenyl or w) -Z-SO₂-het′;

aryl′ is phenyl, naphthyl or biphenyl;

het′ is a 5-, 6- or 7-membered saturated, partially saturated orunsaturated ring containing from one (1) to three (3) heteroatomsindependently selected from the group consisting of nitrogen, oxygen andsulfur; and including any bicyclic group in which any of the aboveheterocyclic rings is fused to a benzene ring or another heterocycle;

provided that:

1) X—R₁ is other than hydrogen or methyl;

2) when R₉ and R₁₀ are substituents on the A-ring, they are other thanmono- or di-methoxy;

3) when R₂ and R₃ are taken together to form ═CHR₁₁ or ═O wherein R₁₁ isO)(C₁-C₆)alkyl, then —X—R, is other than (C₁-C₄)alkyl;

4) when R₂ and R₃ taken together are C═O and R₉ is hydrogen on theA-ring; or when R₂ is hydroxy, R₃ is hydrogen and R₉ is hydrogen on theA-ring, then R₁₀ is other than —O—(C₁-C₆)alkyl or —O—CH₂-phenyl at the2-position of the A-ring;

5) when X—R₁ is (C₁-C₄)alkyl, (C₂-C₄)alkenyl or (C₂-C₄)alkynyl, R₉ andR₁₀ other than mono-hydroxy or ═O, including the diol form thereof, whentaken together; and

6) when X is absent, R₁ is other than a moiety containing a heteroatomindependently selected from N, O or S directly attached to the junctureof the B-ring and the C-ring. (See Published International PatentApplication number WO00/66522)

Each of the glucocorticoid receptor antagonists referenced above andother glucocorticoid receptor antagonists can be used in combinationwith the compounds of the present invention to treat or preventdiabetes, hyperglycemia, hypercholesterolemia, hypertension,hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.

The compounds of the present invention can also be used in combinationwith sorbitol dehydrogenase inhibitors. Sorbitol dehydrogenaseinhibitors lower fructose levels and have been used to treat or preventdiabetic complications such as neuropathy, retinopathy, nephropathy,cardiomyopathy, microangiopathy, and macroangiopathy. U.S. Pat. Nos.5,728,704 and 5,866,578 disclose compounds and a method for treating orpreventing diabetic complications by inhibiting the enzyme sorbitoldehydrogenase.

Each of the sorbitol dehydrogenase inhibitors referenced above and othersorbitol dehydrogenase inhibitors can be used in combination with thecompounds of the present invention to treat diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, cataracts, hyperglycemia, hypercholesterolemia,hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, ortissue ischemia.

The compounds of the present invention can also be used in combinationwith sodium-hydrogen exchanger type 1 (NHE-1) inhibitors. NHE-1inhibitors can be used to reduce tissue damage resulting from ischemia.Of great concern is tissue damage that occurs as a result of ischemia incardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen,pancreas, nerve, spinal cord, retina tissue, the vasculature, orintestinal tissue. NHE-1 inhibitors can also be administered to preventperioperative myocardial ischemic injury.

Examples of NHE-1 inhibitors include a compound having the Formula Ic

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor of said prodrug, wherein

Z is carbon connected and is a five-membered, diaza, diunsaturated ringhaving two contiguous nitrogens, said ring optionally mono-, di-, ortri-substituted with up to three substituents independently selectedfrom R¹, R² and R³; or

Z is carbon connected and is a five-membered, triaza, diunsaturatedring, said ring optionally mono- or di-substituted with up to twosubstituents independently selected from R⁴ and R⁵;

wherein R¹, R², R³, R⁴ and R⁵ are each independently hydrogen,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkyl, (C₁-C₄)alkylthio, (C₃-C₄)cycloalkyl,(C₃-C₇)cycloalkyl(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₁-C₄)alkyl,mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl, M or M(C₁-C₄)alkyl, any of saidprevious (C₁-C₄)alkyl moieties optionally having from one to ninefluorines; said (C₁-C₄)alkyl or (C₃-C₄)cycloakyl optionally mono-ordi-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,(C₁-C₄)alkyl, mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl or mono-N- ordi-N,N-(C₁-C₄)alkylaminosulfonyl; and said (C₃-C₄)cycloalkyl optionallyhaving from one to seven fluorines;

wherein M is a partially saturated, fully saturated or fully unsaturatedfive to eight membered ring optionally having one to three heteroatomsselected independently from oxygen, sulfur and nitrogen, or, a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to our heteroatoms selected independently fromnitrogen, sulfur and oxygen;

said M is optionally substituted, on one ring if the moiety ismonocyclic, or one or both rings if the moiety is bicyclic, on carbon ornitrogen with up to three substituents independently selected from R⁶,R⁷ and R⁸, wherein one of R⁶, R⁷ and R³ is optionally a partiallysaturated, fully saturated, or fully unsaturated three to seven memberedring optionally having one to three heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen optionally substituted with(C₁-C₄)alkyl and additionally R⁶, R⁷ and R⁸ are optionally hydroxy,nitro, halo, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkyl, formyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkanoyloxy, (C₁-C₄)alkanoylamino,(C₁-C₄)alkoxycarbonylamino, sulfonamido, (C₁-C₄)alkylsulfonamido, amino,mono-N- or di-N,N-(C₁-C₄)alkylamino, carbamoyl, mono-N- ordi-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, (C₁-C₄)alkylthio,(C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, mono-N- ordi-N,N-(C₁-C₄)alkylaminosulfonyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl or(C₅-C₇)cycloalkenyl,

wherein said (C₁-C₄)alkoxy, (C₁-C₄)alkyl, (C₁-C7)alkanoyl,(C₁-C₄)alkylthio, mono-N- or di-N,N-(C₁-C₄)alkylamino or(C₃-C₇)cycloalkyl R⁶, R⁷ and R⁸substituents are optionally mono-substituted independently with hydroxy, (C₁-C₄)alkoxycarbonyl,(C₃-C₇)cycloalkyl, (C₁-C₄)alkanoyl, (C₁-C₄)alkanoylamino,(C₁-C₄)alkanoyloxy, (C₁-C₄)alkoxycarbonylamino, sulfonamido,(C₁-C₄)alkylsulfonamido, amino, mono-N- or di-N,N-(C₁-C₄)alkylamino,carbamoyl, mono-N- or di-N,N-(C₁-C₄)alkylcarbamoyl, cyano, thiol, nitro,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl or mono-N-or di-N,N-(C₁-C₄)alkylaminosulfonyl or optionally substituted with oneto nine fluorines. (See PCT patent application number PCT/IB99/00206)

Each of the NHE-1 inhibitors referenced above and other NHE-1 inhibitorscan be used in combination with the compounds of the present inventionto treat or prevent diabetes, insulin resistance, diabetic neuropathy,diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia,hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia,atherosclerosis, or tissue ischemia.

The examples presented below are intended to illustrate particularembodiments of the invention, and are not intended to limit the scope ofthe specification, including the claims, in any manner. All patents,patent applications, and other references cited in this application arehereby incorporated by reference.

Biological Protocols

The utility of the compounds of the present invention as medical agentsin the treatment or prevention of diseases (such as are detailed herein)in animals, particularly mammals (e.g. humans) is demonstrated by theactivity of the compounds of this invention in conventional assays andthe in vitro and in vivo assays described below. Such assays alsoprovide a means whereby the activities of the compounds of thisinvention can be compared with the activities of other known compounds.The results of these comparisons are useful for determining dosagelevels in animals, particularly mammals, including humans, for thetreatment of such diseases.

Glycogen Phosphorylase Production and Assays

The three different purified glycogen phosphorylase (GP) isoenzymes,wherein glycogen phosphorylase is in the activated “a” state (referredto as glycogen phosphorylase a, or the abbreviation GPa), and referredto here as human liver glycogen phosphorylase a (HLGPa), human muscleglycogen phosphorylase a (HMGPa), and human brain glycogen phosphorylasea (HBGPa), can be obtained by the following procedures.

Expression and Fermentation The HLGP cDNAs (obtained as described inNewgard et al., Proc. Natl. Acad. Sci., 83: 8132-8136 (1986), andNewgard et al., Proc. Natl. Acad. Sci., 263: 3850-3857 (1988).respectively) and HMGP cDNAs (obtained by screening a Stratagene(Stratagene Cloning-Systems, La Jolla, Calif.) human muscle cDNA librarywith a polymerase chain reaction (PCR)-generated cDNA fragment based oninformation and methodology reported for isolation of the human skeletalmuscle glycogen phosphorylase gene and partial cDNA-sequence by Kubischet al., Center for Molecular Neurobiology, University of Hamburg,Martinistrasse 85,Hamburg, 20246 Germany; Genbank (National Center forBiotechnology Information, National Institutes of Health, USA) AccessionNumbers U94774, U94775, U94776 and U94777, submitted Mar. 20, 1997;Burke et al., Proteins, 2:177-187 (1987); and Hwang et al., Eur. J.Biochem., 152: 267-274 (1985)) are expressed from plasmid pKK233-2(Pharmacia Biotech. Inc., Piscataway, N.J.) in E. coli strain XL-1 Blue(Stratagene Cloning Systems, LaJolla, Calif.). The strain is inoculatedinto LB medium (consisting of 10 g tryptone, 5 g yeast extract, 5 gNaCl, and 1 ml 1N NaOH per liter) plus 100 mg/L ampicillin, 100 mg/lpyridoxine and 600 mg/L MnCl₂ and grown at 37° C. to a cell density ofOD₅₅₀=1.0. At this point, the cells are induced with 1 mMisopropyl-1-thio-β-D-galactoside (IPTG). Three hours after induction thecells are harvested by centrifugation and cell pellets are frozen at−70° C. until needed for purification.

The HBGP cDNA can be expressed by several methodologies, for example, bythe method described by Crerar, et al. (J. Biol. Chem. 270:13748-13756(1995)). The method described by Crerar, et al. (J. Biol. Chem.,270:13748-13756 (1995)) for the expression of HBGP is as follows: theHBGP cDNA can be expressed from plasmid pTACTAC in E. coli strain 25A6.The strain is inoculated into LB medium (consisting of 10 g tryptone, 5g yeast extract, 5 g NaCl, and 1 ml 1N NaOH per liter) plus 50 mg/Lampicillin and grown overnight, then resuspended in fresh LB medium plus50 mg/L ampicillin, and reinoculated into a 40×volume of LB/amp mediacontaining 250 μM isopropyl-1-thio-β-D-galactoside (IPTG), 0.5 mMpyridoxine and 3 mM MnCl₂ and grown at 22° C. for 48-50 hours. The cellscan then be harvested by centrifugation and cell pellets are frozen at−70° C. until needed for purification.

The HLGP cDNA is expressed from plasmid pBlueBac IlIl (Invitrogen Corp.,San Diego, Calif.) which is cotransfected with BaculoGold Linear ViralDNA (Pharmingen, San Diego, Calif.) into Sf9 cells. Recombinant virus issubsequently plaque-purified. For production of protein, Sf9 cells grownin serum-free medium (Sf-900 II serum free medium, Gibco BRL, LifeTechnologies, Grand Island, N.Y.) are infected at an moi of 0.5 and at acell density of 2×10⁶ cells/ml. After growth for 72 hours at 27° C.,cells are centrifuged, and the cell pellets frozen at −70° C. untilneeded for purification.

Purification of Glycogen Phosphorylase expressed in E coli

The E. coli cells in pellets described above are resuspended in 25 rnMβ-glycerophosphate (pH 7.0) with 0.2 mM DTT,1 mM MgCl₂, plus thefollowing protease inhibitors: 0.7 μg/ml Pepstatin A 0.5 μg/ml Leupeptin0.2 mM phenylmethylsulfonyl fluoride (PMSF), and 0.5 mM EDTA,lysed by pretreatment with 200 μg/ml lysozyme and 3 μg/ml DNAasefollowed by sonication in 250 ml batches for 5×1.5 minutes on ice usinga Branson Model 450 ultrasonic cell disrupter (Branson Sonic Power Co.,Danbury Conn.). The E. coli cell lysates are then cleared bycentrifugation at 35,000×g for one hour followed by titration through0.45 micron filters. GP in the soluble fraction of the lysates(estimated to be less than 1% of the total protein) is purified bymonitoring the enzyme activity (as described in GPa Activity Assaysection, below) from a series of chromatographic steps detailed below.Immobilized Metal Affinity Chromatography (IMAC)

This step is based on the method of Luong et al (Luong et al. Journal ofchromatography 584: 77-84 (1992)). Five hundred ml of the filteredsoluble fraction of cell lysates (prepared from approximately 160-250 gof original cell pellet) are loaded onto a 130 ml column of IMACChelating-Sepharose (Pharmacia LKB Biotechnology, Piscataway, NewJersey) which has been charged with 50 mM CuCl₂ and 25 mMβ-glycerophosphate, 250 mM NaCl and 1 mM imidazole at pH 7(equilibration buffer). The column is washed with equilibration bufferuntil the A₂₈₀ returns to baseline. The sample is then eluted from thecolumn with the same buffer containing 100 mM imidazole to remove thebound GP and other bound proteins. Fractions containing the GP activityare pooled (approximately 600 ml), and ethylenediaminetetraacetic acid(EDTA), DL-dithiothreitol (DTT), phenylmethylsulfonyl fluoride (PMSF),leupeptin and pepstatin A are added to obtain 0.3 mM, 0.2 mM, 0.2 mM,0.5 μg/ml and 0.7,μ/ml concentrations respectively. The pooled GP isdesalted over a Sephadex G-25 column (Sigma Chemical Co., St. Louis,Mo.) equilibrated with 25 mM Tris-HCl .(pH 7.3), 3 mM DTT buffer (BufferA) to remove imidazole and is stored on ice and subjected to a secondchromatographic step (below) if necessary.

5′-AMP-Sepharose Chromatography

The desalted pooled GP sample (approximately 600 mL).is next mixed with70 ml of 5′-AMP Sepharose (Pharmacia LKB Biotechnology, Piscataway,N.J.) which has been equilibrated with Buffer A (see above). The mixtureis gently agitated for one hour at 22° C. then packed into a column andwashed with Buffer A until the A₂₈₀ returns to baseline. GP and otherproteins are eluted from the column with 25 mM Tris-HCl, 0.2 mM DTT and10 mM adenosine 5′-monophosphate (AMP) at pH 7.3 (Buffer B).GP-containing fractions are pooled following identification bydetermining enzyme activity described below and visualizing the M_(r)approximately 97 kdal GP protein band by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) followed by silverstaining (2D-silver Stain II “Daiichi Kit”, Daiichi Pure Chemicals Co.,LTD., Tokyo, Japan) and then pooled. The pooled GP is dialyzed into 25mM β-glycerophosphate, 0.2 mM DTT, 0.3 mM EDTA, 200 mM NaCl, pH 7.0buffer (Buffer C) and stored on ice until use.

Prior to use of the GP enzyme, the enzyme is converted from the inactiveform as expressed in E. coil strain XL-1 Blue (designated GPb) (StrageneCloning Systems, La Jolla, Calif.), to the active form (designated GPa)by the procedure described in Section (A) Activation of GP below.

Purification of Glycogen Phosphorylase Expressed in Sf9 Cells

The Sf9 cells in pellets described above are resuspended in 25 mMβ-glycerophosphate (pH 7.0) with 0.2 mM DTT, 1 mM MgCl2, plus thefollowing protease inhibitors: 0.7 μg/ml Pepstatin A 0.5 μg/ml Leupeptin0.2 mM phenylmethylsulfonyl fluoride (PMSF), and 0.5 mM EDTA,lysed by pretreatment with 3 μg/ml DNAase followed by sonication inbatches for 3×1 minutes on ice using a Branson Model 450 ultrasonic celldisrupter (Branson Sonic Power Co., Danbury Conn.). The Sf9 cell lysatesare then cleared by centrifugation at 35,000×g for one hour followed byfiltration through 0.45 micron filters. GP in the soluble fraction ofthe lysates (estimated to be 1.5% of the total protein) is purified bymonitoring the enzyme activity (as described in GPa Activity Assaysection, below) from a series of chromatographic steps detailed below.Immobilized Metal Affinity Chromatography (IMAC)

Immobilized Metal Affinity Chromatography is performed as described inthe section above. The pooled, desalted GP Is then stored on ice untilfurther processed.

Activation of GP

Before further chromatography, the fraction of inactive enzyme asexpressed in Sf9 cells (designated GPb) is converted to the active form(designated GPa) by the following procedure described in Section (A)Activation of GP below.

Anion Exchange Chromatography

Following activation of the IMAC purified GPb to GPa by reaction withthe immobilized phosphorylase kinase, as described below, the pooled GPafractions are dialyzed against 25 mM Tris-HCl, pH 7.5, containing 0.5 mMDTT, 0.2 mM EDTA, 1.0 mM phenylmethylsulfonyl fluoride (PMS F), 1.0μg/ml leupeptin and 1.0 μg/ml pepstatin A. The fraction is then loadedonto a MonoQ Anion Exchange Chromatography column (Pharmacia Biotech.Inc., Piscataway, N.J.). The column is washed with equilibration bufferuntil the A₂₈₀ returns to baseline. The Sample is then eluted from thecolumn with a linear gradient of 0-0.25 M NaCl to remove the bound GPand other bound proteins. GP-containing fractions eiute between 0.1-0.2M NaCl range, as detected by monitoring the eluant for peak proteinabsorbance at A₂₈₀. The GP protein is then identified by visualizing theM_(r) approximately 97 kdal GP protein band by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) followed by silverstaining (2D-silver Stain II “Daiichi Kit”, Daiichi Pure Chemicals Co.,LTD., Tokyo, Japan) and then pooled. The pooled GP is dialyzed into 25mM N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 1.0 mMDTT, 0.5 mM EDTA, 5 mM NaCl, pH 6.8 buffer and stored on ice until use.

Determination of GP Enzyme Activity

A) Activation of GP: Conversion of GPb to GPa

Prior to the determination of GP enzyme activity, the enzyme isconverted from the inactive form as expressed in E. coli strain XL-1Blue (designated GPb) (Stragene Cloning Systems, La Jolla, Calif.), tothe active form (designated GPa) by phosphorylation of GP usingphosphorylase kinase as follows. The fraction of inactive enzyme asexpressed in Sf9 cells (designated GPb) is also converted to the activeform (designated GPa) by the follow procedure.

I G.P reaction with Immobilized Phosphorylase Kinase

Phosphorylase kinase (Sigma Chemical Company, St. Louis, Mo.) isimmobilized on Affi-Gel® 10 (BioRad Corp., Melvile, N.Y.) as per themanufacturer's instructions. In brief, the phosphorylase kinase enzyme(10 mg) is incubated with washed Affi-Gel® beads (1 ml) in 2.5 ml of 100mM HEPES and 80 mM CaCl₂ at pH 7.4 for 4 hours at 4° C. The Affi-Gel®beads are then washed once with the same buffer prior to blocking with50 mM HEPES and 1 M glycine methyl ester at pH 8.0 for one hour at roomtemperature. Blocking buffer is removed and replaced with 50 mM HEPES(pH 7.4), 1 mM B-mercaptoethanol and 0.2% NaN₃ for storage. Prior to useto convert GPb to GPa, the Affi-Gel® immobilized phosphorylase kinasebeads are equilibrated by washing in the buffer used to perform thekinase reaction, consisting of 25 mM β-glycerophosphate, 0.3 mM DTT, and0.3mM FDTA at pH 7.8 (kinase assay buffer).

The partially purified, inactive GPb obtained from 5′-AMP-Sepharosechromatography above (from E. coli) or the mixture of GPa and GPbobtained from IMAC above (from Sf9 cells) is diluted 1:10 with thekinase assay buffer then mixed with the aforementioned phosphorylasekinase enzyme immobilized on the Affi-Gel® beads. NaATP is added to 5 mMand MgCl₂ to 6 mM. The resulting mixture is mixed gently at 25° C. for30 to 60 minutes. The activated sample is removed from the beads and thepercent activation of GPb by conversion to GPa is estimated bydetermining GP enzyme activity in the presence and absence of 3.3 mMAMP. The percentage of total GP enzyme activity due to GPa enzymeactivity (AMP-independent) is then calculated as follows:${\%\quad{of}\quad{total}\quad{HLGPa}} = \frac{{{HLGP}\quad{activity}} - {AMP}}{{{HLGP}\quad{activity}} + {AMP}}$

Alternately, the conversion of GPb to GPa can be monitored byisoelectric focusing, based on the shift in electrophoretic mobilitythat is noted following conversion of GPb to GPa. GP samples areanalyzed by isoelectric focusing (IEF) utilizing the Pharmacia PfastGelSystem (Pharmacia Biotech. Inc., Piscataway, N.J.) using precast gels(pl range 4-6.5) and the manufacturer's recommended method. The resolvedGPa and GPb bands are then visualized on the gels by silver staining(2D-silver Stain II “Daiichi Kit”, Daiichi Pure Chemicals Co., LTD.,Tokyo, Japan). Identification of GPa and GPb is made by comparison to E.coli derived GPa and GPb standards that are run in parallel on the samegeis as the experimental samples.

B) GPa Activity Assay

The disease/condition treating/preventing activities described herein ofthe compounds of the present invention can be indirectly determined byassessing the effect of the compounds of this invention on the activityof the activated form of glycogen phosphorylase (GPa) by one of twomethods; glycogen phosphorylase a activity is measured in the forwarddirection by monitoring the production of glucose-1-phosphate fromglycogen or by following the reverse reaction, measuring glycogensynthesis from glucose-1-phosphate by the release of inorganicphosphate. All reactions are run in triplicate in 96-well microtiterplates and the change in absorbance due to formation of the reactionproduct is measured at the wavelength specified below in a MCC/340 MKIIElisa Reader (Lab Systems, Finland), connected to a Titertech MicroplateStacker (ICN Biomedical Co, Huntsville, Ala.).

To measure the GPa enzyme activity in the forward direction, theproduction of glucose-1-phosphate from glycogen is monitored by themultienzyme coupled general method of Pesce et al. [Pesce, M. A.,Bodourian, S. H., Harris, R. C. and Nicholson, J. F. Clinical Chemistry23: 1711-1717 (1977)] modified as follows: 1 to 100 μg GPa, 10 unitsphosphoglucomutase and 15 units glucose-6-phosphate dehydrogenase(Boehringer Mannheim Biochemicals, Indianapolis, Id.) are diluted to 1mL in Buffer D (pH 7.2, 50 mM HEPES, 100 mM KCl, 2.5 mMethyleneglycoltetraacetic acid (EGTA), 2.5 mM MgCl₂, 3.5 mM KH₂PO₄ and0.5 mM dithiothreitol). Twenty μl of this stock is added to 80 μl ofBuffer D containing 0.47 mg/mL glycogen, 9.4 mM glucose, 0.63 mM of theoxidized form of nicotinamide adenine dinucleotide phosphate (NADP+).The compound to be tested is added as 5 μl of solution in 14%dimethylsulfoxide (DMSO) prior to the addition of the enzymes. The basalrate of GPa enzyme activity in the absence of inhibitors, e.g., acompound of this invention, is determined by adding 5 μl of 14% DMSO anda fully-inhibited rate of GPa enzyme activity is obtained by adding 20μl of 50 mM of the positive control test substance, caffeine. Thereaction is followed at room temperature by measuring the conversion ofoxidized NADP+to reduced NADPH at 340 nm.

To measure the GPa enzyme activity in the reverse direction, theconversion of glucose-1-phosphate into glycogen plus inorganic phosphateis measured by the general method described by Engers et al. [Engers, H.D., Shechosky, S. and Madsen, N. B., Can. J. Biochem. 48: 746-754(1970)] modified as follows: 1 to 100 μg GPa is diluted to 1 ml inBuffer E (pH 7.2, 50 mM HEPES, 100 mM KCI, 2.5 mM EGTA, 2.5 mM MgCl₂ and0.5 mM dithiothreitol). Twenty μl of this stock is added to 30 μl ofBuffer E with 1.25 mg/ml glycogen, 9.4 mM glucose, and 0.63 mMglucose-1-phosphate. The compound to be tested is added as 5 μl ofsolution in 14% DMSO prior to the addition of the enzyme. The basal rateof GPa enzyme activity in the absence of added inhibitors, e.g., acompound of this invention, is determined by adding 5 μl of 14% DMSO anda fully-inhibited rate of GPa enzyme activity is obtained by adding 20μL of 50 mM caffeine. This mixture is incubated at room temperature for1 hour and the inorganic phosphate released from the glucose-1-phosphateis measured by the general method of Lanzetta et al. [Lanzetta, P. A.,Alvarez, L. J., Reinach, P. S. and Candia, O. A. Anal. Biochem. 100:95-97 (1979)] modified as follows: 150 μl of 10 mg/ml ammoniummolybdate, 0.38 mg/ml malachite green in 1 N HCl is added to 100 μl ofthe enzyme mix. After a 20 minute incubation at room temperature, theabsorbance is measured at 620 nm.

The above assays carried out with a range of concentrations of testcompound allows the determination of an IC₅₀ value (concentration oftest compound required for 50% inhibition) for the in vitro inhibitionof GPa enzyme activity by that test compound.

The compounds of this invention are readily adapted to clinical use ashypoglycemic agents. The hypoglycemic activity of the compounds of thisinvention can be determined by the amount of test compound that reducesglucose levels relative to a vehicle without test compound in male ob/obmice. The test also allows the determination of an approximate minimaleffective dose (MED) value for the in vivo reduction of plasma glucoseconcentration in such mice for such test compounds.

Since the concentration of glucose in blood is closely related to thedevelopment of diabetic disorders, the compounds of the presentinvention, by virtue of their hypoglycemic action, prevent, arrestand/or regress diabetic disorders.

Five to eight week old male C57BL6J-ob/ob mice (obtained from JacksonLaboratory, Bar Harbor, Me.) are housed five per cage under standardanimal care practices. After a one week acclimation period, the animalsare weighed and 25 microliters of blood are collected from theretro-orbital sinus prior to any treatment.

The blood sample is immediately diluted 1:5 with saline containing0.025% sodium heparin, and held on ice for metabolite analysis. Animalsare assigned to treatmnent groups so that each group has a similar meanfor plasma glucose concentration. After group assignment, animals aredosed orally each day for four days with the vehicle consisting ofeither: (1) 0.25% w/v methyl cellulose in water without pH adjustment;or (2) 0.1% Pluronic® P105 Block Copolymer Surfactant (BASF Corporation,Parsippany. N.J.) in 0.1% saline without pH adjustment. On day 5, theanimals are weighed again and then dosed orally with a test compound orthe vehicle alone. All compounds are administered in vehicle consistingof either: (1) 0.25% w/v methyl cellulose in water; or 3) neat PEG 400without pH adjustment; (2) 10% DMSO/0.1% Pluronic® in 0.1% salinewithout pH adjustment; or 3) neat PEG 400 without pH adjustment. Theanimals are then bled from the reto-orbital sinus three hours later fordetermination of blood metabolite levels. The freshly collected samplesare centrifuged for two minutes at 10,000×g at room temperature. Thesupernatant is analyzed for glucose, for example, by the Abbott VP™(Abbott Laboratories, Diagnostics Division, Irving, Tex.) and VP SuperSystem™ Autoanalyzer (Abbott Laboratories, Irving, Tex.), or by theAbbott Spectrum CCX™ (Abbott Laboratories, Irving, Tex.) using theA-Gent™ Glucose-UV Test reagent system (Abbott Laboratories, Irving,Tex.) (a modification of the method of Richterich and Dauwalder,Schweizerische Medizinische Wochenschrift, 101: 860 (1971)) (hexokinasemethod) using a 100 mg/dl standard. Plasma glucose is then calculated bythe equation: Plasma glucose (mg/dl)=Sample value×8.14

where 8.14 is the dilution factor, adjusted for plasma hematocrit(assuming the hematocrit is 44%).

The animals dosed with vehicle maintain substantially unchangedhyperglycemic glucose levels (e.g., greater than or equal to 250 mg/dl),animals treated with compounds having hypoglycemic activity at suitabledoses have significantly depressed glucose levels. Hypoglycemic activityof the test compounds is determined by statistical analysis (unpairedt-test) of the mean plasma glucose concentration between the testcompound group and vehicle-treated group on day 5.

The above assay carried out with a range of doses of a test compoundallows the determination of an approximate minimal effective dose (MED)value for the in vivo reduction of plasma glucose concentration.

The compounds of the present invention are readily adapted to clinicaluse as hyperinsulinemia reversing agents, triglyceride lowering agentsand hypocholesterolemic agents. Such activity can be determined by theamount of test compound that reduces insulin, triglycerides orcholesterol levels relative to a control vehicle without test compoundin male ob/ob mice.

Since the concentration of cholesterol in blood is closely related tothe development of cardiovascular, cerebral vascular or peripheralvascular disorders, the compounds of this invention, by virtue of theirhypocholesterolemic action, prevent, arrest and/or regressatherosclerosis.

Since the concentration of insulin in blood is related to the promotionof vascular cell growth and increased renal sodium retention, (inaddition to the other actions, e.g., promotion of glucose utilization)and these functions are known causes of hypertension, the compounds ofthis invention, by virtue of their hypoinsulinemic. action, prevent,arrest and/or regress hypertension.

Since the concentration of triglycerides in blood contributes to theoverall levels of blood lipids, the compounds of this invention, byvirtue of their triglyceride lowering and/or free fatty acid loweringactivity prevent, arrest and/or, regress hyperlipidemia.

Free fatty acids contribute to the overall level of blood lipids andindependently have been negatively correlated with insulin sensitivityin a variety of physiologic and pathologic states.

Five to eight week old male C57BL/6J-ob/ob mice (obtained from JacksonLaboratory, Bar Harbor, Me.) are housed five per cage under standardanimal care practices and fed standard rodent diet ad libitum. After aone week acclimation period, the animals are weighed and 25 microlitersof blood are collected from the retro-orbital sinus prior to anytreatment. The blood sample is immediately diluted 1:5 with salinecontaining 0.025% sodium heparin, and held on ice for plasma glucoseanalysis. Animals are assigned to treatment groups so that each grouphas a similar mean for plasma glucose concentration. The compound to betested is administered by oral gavage as an about 0.02% to 2.0% solution(weight/volume (w/v)) in either (1) 10% DMSO/0.1% Pluronic® P105 BlockCopolymer Surfactant (BASF Corporation, Parsippany, N.J.) in 0.1% salinewithout pH adjustment or (2) 0.25% w/v methylcellulose in water withoutpH adjustment. Alternatively, the compound to be tested can beadministered by oral gavage dissolved in or in suspension in neat PEG400. Single daily dosing (s.i.d.) or twice daily dosing (b.i.d.) ismaintained for 1 to, for example, 15 days. Control mice receive the 10%DMSO/0.1% Pluronic® P105 in 0.1% saline without pH adjustment or the0:25% w/v methylcellulose in water without pH adjustment, or the neatPEG 400 without pH adjustment.

Three hours after the last dose is administered, the animals aresacrificed by decapitation and trunk blood is collected into 0.5 mlserum separator tubes containing 3.6 mg of a 1:1 weight/weight sodiumfluoride: potassium oxalate mixture. The freshly collected samples arecentrifuged for two minutes at 10,000×g at room temperature, 2(0 And theserum supernatant is transferred and diluted 1:1 volume/volume with a 1TIU/ml aprotinin solution in 0.1% saline without pH adjustment.

The diluted serum samples are then stored at −80° C. until analysis. Thethawed, diluted serum samples are analyzed for insulin, triglycerides,free fatty acids and cholesterol levels. Serum insulin concentration isdetermined using Equate® RIA INSULIN kits (double antibody method; asspecified by the manufacturer) available from Binax, South Portland, Me.The inter assay coefficient of variation is ≧10%. Serum triglyceridesare determined using the Abbott VP™ and VP Super System® Autoanalyzer(Abbott Laboratories, Irving, Tex.), or the Abbott Spectrum CCX™ (AbbottLaboratories, Irving, Tex.) using the A-Gent™ Triglycerides Test reagentsystem (Abbott Laboratories, Diagnostics Division, lrving, Tex.)(lipase-coupled enzyme method; a modification of the method of Sampson,et al., Clinical Chemistry 21: 1983 (1975)). Serum total cholesterollevels are determined using the Abbott VP™ and VP Super System°Autoanalyzer (Abbott Laboratories, Irving, Tex.), and A-Gent™Cholesterol Test reagent system (cholesterol esterase-coupled enzymemethod; a modification of the method of Allain, et al. ClinicalChemistry 20: 470 (1974)) using 100 and 300 mg/dl standards. Serum freefatty acid concentration is determined utilizing a kit from AmanoInternational Enzyme Co., Inc., as adapted for use with the Abbott VP™and VP Super System® Autoanalyzer (Abbott Laboratories, Irving, Tex.),or the Abbott Spectrum CCX™ (Abbott Laboratories, Irving, Tex.). Seruminsulin, triglycerides, free fatty acids and total cholesterol levelsare then calculated by the equations,

Serum insulin (μU/ml)=Sample value×2

Serum triglycerides (mg/dl)=Sample value×2

Serum total cholesterol (mg/dl)=Sample value×2

Serum free fatty acid (μEq/l)=Sample value×2

where 2 is the dilution factor.

The animals dosed with vehicle maintain substantially unchanged,elevated serum insulin (e.g., 275 μU/ml), serum triglycerides (e.g., 235mg/dl), serum free fatty acid (1500 mEq/ml) and serum total cholesterol(e.g., 190 mg/dl) levels, while animals treated with compounds of thepresent invention generally display reduced serum insulin,triglycerides, free fatty acid and total cholesterol levels. The seruminsulin, triglycerides, free fatty acid and total cholesterol loweringactivity of the test compounds are determined by statistical analysis(unpaired t-test) of the mean serum insulin, triglycerides, or totalcholesterol concentration between the test compound group and thevehicle-treated control group.

The present invention is illustrated by the following examples, but itis not limited to the details thereof.

PREPARATIONS Preparation 1 Methyl 2,3-dihydroxy benzoate

A mixture of 92.472 g (0.6 mol) of 2,3-dihydroxybenzoic acid (FW 154.12;Aldrich cat.# 12,620-9; RSO # 9449), 100 mL of anhydrous methanol and 3mL of concentrated sulfuric acid was heated to reflux for 36 hrs. Aftercooling down, reaction mixture was concentrated down to approximately ⅓of its volume and poured on ice. A precipitate that formed was washedthoroughly with cold water, filtered off and dried in the desiccatorover calcium sulfate. Yield 98.4 g of off-white solid (98%). This wasused without further purification.

LC MS: AP⁺ 169, AP⁻ 167.

Preparation 2 3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acidmethyl ester

A flame dried 1 L-flask was charged with 82.7 grams (0.6 mol) of finelyground and flame dried potassium carbonate and 200 mL of absolutedimethylformamide and kept under-nitrogen gas. This reaction mixture wasthen stirred and warmed up to 40° C. A 47.23 g (29.7 mL, 0.3 mol) of1-bromo-3-chloropropane was then added to the reaction flask rapidlyfollowed by 50.445 g (0.3 mol) of methyl 2,3-dihydroxy benzoate (C-2).The reaction was then heated to 100° C. (110° C. was the temp. of an oilbath) under reflux condenser for 6 hrs. After cooling, the reaction wasfiltered to remove all the solids, solids washed with 50 mL of, DMF andfiltrate concentrated on the rotary evaporator. The residue was thenpartitioned between water and ethyl acetate. The organic layer was thenwashed with 200 mL of 1N NaOH to remove any starting material, followedby 5% HCl, 5% NaHCO₃, water and brine. Dried with magnesium sulfate.Filtered, stripped. Crude 5.63 grams. The product was then purified bythe means of flash chromatography (400 g of silica gel: 20%AcOEt/hexanes). Collected 38.54 g (62%) as clear oil. LC MS: AP⁺ 209.AP⁻ 207.

Preparation 3 8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester (C-4) and 9-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methylester (C-5)

A 17.15 g (0.0825 mol) of(3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester;C-3) was dissolved in a mixture of 65 mL of glacial acetic acid and 65mL of acetic anhydride. The reaction mixture was heated to 45° C. andtreated with a solution of 12 mL of 90% HNO₃ (fuming) inl2 mL of glacialacetic acid dropwise. The reaction was then heated to 45-50° C. for 4hours under reflux condenser. When cooled down, the reaction mixture waspoured on a mix of ice and water and the yellow precipitate collected ona filter. Washed with water and dried on air. Crude 17.6 grams (thisproduct was a mixture of the meta- (about 30%). and paranitration (about60%) products. This was used without further purification. LC MS: AP⁻253 (for the mixture)

Preparation 4 Purification of Intermediate C-5 and Preparation of acidintermediate C-6Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methylester (C-5): 8Nitro-3,4-dihydro-2H-benzo[b][1,4dioxepine-6-carboxylicacid (C-6)

The solid collected from Preparation 3 (17.6 g) was combined with 2.8 gof sodium hydroxide in a 1:4 mixture of THF and water. The reactionmixture was stirred at room temperature overnight and the solid thatfilled the flask collected on a filter to yield 8.6 g of un-hydrolyzedester C-6 (LCMS: AP⁻ 253). The filtrate was acidified with concentratedHCl and the yellow solid collected on a filter to yield 7.04 g ofcarboxylic acid of C-6. Recrystallized from ethyl acetate to give C-6 asyellow needles (5.96 g). LC MS: AP⁻ 238.

Preparation 5 Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester

A mixture of 8-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester (0.58 g), SnCl₂ (2.17 g) and ethanol was refluxed at70° C. for 2 hours. The reaction was poured over ice and the resultingaqueous solution treated with 5% NaHCO₃ (pH 7-8) and extracted withEtOAc. The organic phase was dried with MgSO₄ and solvent removed invacuo to yield 0.318 g of product which was used directly in the nextreaction. MS: M⁺ 224.

Preparation 6 Intermediates

To a cold CH₂Cl₂ (2.3 mL) solution of8-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid (C-6;2.31 g) was added 10 mL of a 1M (COCl)₂ solution in methylene chloride.To that mixture was then added 4 drops of DMF. The reaction was stirredat room temperature for 2 hours and used with out further purificationin the following protocols.

To 1.0 mmol of the amine was added 1.0 mmol. of the above prepared acidchloride in dry CH₂Cl₂ containing one drop of DMF. The reaction wasstirred for 2 hours and then diluted with 6N HCl and partitioned betweenEtOAc and water. The organic phase was separated, dried with MgSO₄ andsolvent removed to yield the product.

According to the above procedure, the following nitro amides wereanalogously prepared:

8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid(2-hydroxy-ethyl)-amide

8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid dimethylamide.

5Morpholin-4-yl-(8-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-methanone

(8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperidin-1-yl-methanone

(8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-thiomorpholin-4-yl-methanone

8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic aciddiethylamide

(8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-pyrrolidin-1-yl-methanone

(3,4-Dihydroxy-pyrrolidin-1-yl)-(8-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)methanone

(4-Methyl-piperazin-1-yl)-(8-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-methanone

8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid(2-methoxy-ethyl)-amide

8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid(2-hydroxy-ethyl)-amide

Preparation 7

The following amines were further prepared.

8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid(2-hydroxy-ethyl)-amide

8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid dimethylamide.

Morpholin-4-yl-(8-amino-3,4-dihydro-2-H-benzo[b][1,4]dioxepin-6-yl)-methanone

(8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperidin-1-yl-methanone

(8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-thiomorpholin-4-yl-methanone

8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic aciddiethylamide

(8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-pyrrolidin-1-yl-methanone

(3,4-Dihydroxy-pyrrolidin-1-yl)-(8-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-methanone

(4-Methyl-piperazin-1-yl)-(8-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-methanone

8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid(2-methoxy-ethyl)-amide

8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid(2-hydroxy-ethyl)-amide

Preparation 8 8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)methanol

A flame dried flask in an inert atmosphere of dry nitrogen was chargedwith 5.96 g (0.025 mol) of8-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid and 10mL of anhydrous THF. The reaction mixture was cooled in an ice bath and25 mL of 1 M borane tetrahydrofurane complex (0.025 mol) was addedportion-wise via syringe. The reaction was then stirred at roomtemperature for 2 hrs and checked on TLC (only about 60% of conversion).Another 20 mL. of 1 M BH₃. THF (0.02 mol) was then added and reactionstirred for additional 2 hrs at room temperature. After this time, thereaction mixture was carefully quenched with 10 mL of saturated ammoniumchloride and partitioned between ethyl acetate and water. The organicphase washed with 5% NaHCO₃, water, brine, dried with sodium sulfate,filtered and concentrated in vacuo. 4.78 g of crude material wascollected which was recrystallized from boiling toluene. 3.46 g (62%) ofpure material was obtained as yellow needles. LC MS AP⁺ 210 (loss ofwater), AP⁻ 225.

Preparation 9(8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-methanol

2.25 g (0.01 mol) of nitro benzyl alcohol compound was dissolved in amixture of 45 mL of methanol and 45 mL of THF. A solid ammonium formatewas then added (3.18 g, 0.05 mol, 5 equivalents) followed by the carefuladdition of 455 mg of 10% palladium on carbon. The reaction mixture wasthen stirred very slowly at room temperature under reflux condenser.Once it starts, the reaction was rapid and exothermic. After about 1hour the evolution of hydrogen gas ceased and reaction was checked onTLC (more polar product formation, reaction was dome after this time).The crude reaction was then filtered thru celite, the filtrate dilutedwith four times of its volume of diethyl ether. The white precipitatethat formed was filtered off and dried in vacuo. 1.403 g (72%) ofoff-white solid was collected. LC MS: AP⁺ 196

Preparation 10(2-Nitro-7,8-dihydro-6H-5-oxa-9aza-benzocyclohepten-9-yl)-acetic acidethyl ester

Powdered and flame dried potassium carbonate (1.52 g, 11 mmol, 1.1 eq.)was placed in a round bottom flask together with 60 mL of anhydrousdimethylformamide and kept under inert atmosphere.2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (1.942 g, 10mmol, 1 eq.) was dissolved in 20 mL of anhydrous DMF and added to thereaction mixture. The reaction was heated to 120° C. under refluxcondenser for 1 hour and then solution of ethyl bromoacetate (3.34 g,2.22 mL, 20 mmol, 2 eq.) in 5 mL of dry DMF was added dropwise to thehot solution. The reaction mixture was then heated to 120° C. for anadditional 12 hours. When cooled, the DMF was removed on the rotaryevaporator, and diluted with 100 mL of water. The aqueous pnase, waswashed (3×) with 50 mL portions of methylene chloride. The methylenechloride extracts were combined and washed with water and brine anddried over magnesium sulfate. Crude material (3.018 g) waschromatographed on a large-Biotage column in 20% ethyl acetate/hexanes.1.38 g (500% yield) of pure material (bright yellow crystalline powder)was collected. LC MS: AP⁺ 281, AP⁻ 280.

Preparation -11(2-Amino-7,8-dihydro-6H-5-oxa-9aza-benzocyclohepten-9-yl)-acetic acidethyl ester

2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetic acidethyl Aster (841 mg, 3 mmol, 1.0 eq.) was dissolved in 15 mL MeOH and 15mL THF. Eighty mg of 10% Pd/C was carefully added under nitrogentogether with of ammonium formate (946 mg, 15 mmol, 5 eq.). Thestoppered reaction mixture was stirred at room temperature for twohours. The reaction mixture was then diluted with 150 mL of diethylether, filtered through celite and concentrated. The product (oil, 94 mg(75%)) was homogenous by TLC (100% AcOEt, Rf=0.4) and was used withoutfurther purification in the subsequent coupling reactions. LC MS: AP+251.

EXAMPLES Example 1 5-Chloro-1H-Indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

-   1. Reagent preparations:    -   Preparation of a 1M (COCl₂)₂solution in CH₂Cl₂.    -   a. Added 25 g of (COCl₂)₂ to 100 mL of CH₂Cl₂.    -   b. Diluted the solution to 200 mL total volume.-   2. Preparation to 5M acid chloride (5-chloro-1H-lndole-2-carboxylic    acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide), in CH₂Cl₂.    -   a. Added 1M (COCl₂)₂/CH₂Cl₂ (14 mL) to a slurry of        5-chloro-1H-lndole-2-carboxylic acid (2.09 g) in CH₂C₂ (10 mL),        with ice bath cooling.    -   b. Added DMF (0.4 mL) over 5 minutes.    -   c. Stirred at room temperature for 2 hours    -   d. Filtered    -   e. Diluted to 26 mL with CH₂Cl₂.-   3. Aryl amines (100 μM, each) were weighed into ½ dram septum vials,    numbered A1 . . . H6 using a standard 96 well micro titer format.-   4. Pyridine (100 uL) was added to each amine.-   5. DMF (200 mL) was added to each reaction.-   6. The above 0.5M acid chloride solution (0.24 mL, 126 uM) was added    to each.-   7. Reactions were shaken over night.    Purification:-   1. Solvent was removed by a nitrogen stream at 50° C.-   2. Reaction residues were dissolved in DMSO (500 μL) and filtered.-   3. The reaction filtrates were cloned for LCMS.-   4. The filtrates which showed a parent ion were purified by reverse    phase HPLC to afford pure product.    Alternately, each reaction could be prepared in a single reaction    vessel under standard conditions described above and using the same    protocol described above.

Example 28-[(5-Chloro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester

8-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methylester (0.003 g), 5-chloro-1H-lndole-2-carboxylic acid (0.263 g), BOP(0.594), TEA (0.377 mL) and DMF (3.0 mL) were mixed together and stirredfor 4 hours. The reaction was diluted with water and the resultingfiltrate filtered. The resulting solid was tritriated with EtOAc,rinished with the same and purified by flash chromatography (silicagel-25% EtOAc/hexane) to yield 122 mg of the product. MS PDS: M⁺ 401/403

Example 38[-(5-Chloro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid.

8-[(5-Chloro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester (120 mg) was dissolved in a mixture of THF/water and0.3 mL of 1 N KOH. The reaction was stirred at room temperatureovernight, made acidic with 1N HCl and then extracted with EtOAc. Theorganic extract was washed with water, brine and dried with MgOS04. Thisafforded 35 mg of product. MS POS: M⁺ 387/389.

Example 4 9-Amino-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester

To a mixture of9-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methylester (C-5; 2.53 g) and Pd/C (450 mg) suspended in 90 mL of a 1/1mixture of THF/CH₃OH was added HCO₂HN₄ (3.153 g) and the resultingreaction heated to 70° C. for 30 minutes. The reaction was diluted with900 mL of diethyl ether. The resulting solution was filtered throughcelite and the organic solvent removed in vacuo to yield 2.152 g ofwhite crystalline solid. AP⁺ 192 (—OCH₃).

Example 59-[(1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b]1,4]dioxepine-carboxylicacid methyl ester.

LCMS: AP⁺ 365

Example 69-[(5-Fluoro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester.

LCMS:. AP⁺ 385

Example 79-[(5-Chloro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester.

LCMS: AP⁺ 401

Example 89-[(1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid

9-[(1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid methyl ester (E-2; R═H; 50 mg) was combined with 1 mL of THF and 1ml of 1M NaOH and the reaction stirred for 4 days at room temperature.The solid was collected on a filter to yield 23 mg of a solid. LCMS: AP⁺353.

Example 99-[(5-Fluoro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid

LCMS: AP⁺ 371.

Example 109-[(5-Chloro-1H-indole-2-carbonyl)amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid.

LCMS: AP⁺ 387/389.

Example 11

The following compounds were further prepared.

5-Chloro-1H-indole-2-carboxylic acid(9-carbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

5-Chloro-1H-indole-2-carboxylic acid[9-(pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

5-Chloro-1H-indole-2-carboxylic acid(9-dimethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

5-Chloro-1H-indole-2-carboxylic acid(9-diethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

5-Chloro-1H-indole-2-carboxylic acid[9-(pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

5-Chloro-1H-indole-2-carboxylic acid[9-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

5-Chloro-1H-indole-2-carboxylic acid[9-(morpholine-4-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

5-Chloro-1H-indole-2-carboxylic acid[9-(3,4-dihydroxy-pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

5-Chloro-1H-indole-2-carboxylic acid[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

Example 12 5-Chloro-1H-indole-2-carboxylic acid[(9-hydroxymethyl)]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺ 373/375, AP⁻ 371/373

Example 13 5-Chloro-1H-indole-2-carboxylic acid(9diethylaminomethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺ 428/430, AP⁻ 426/428

Example 14 5-Chloro-1H-indole-2-carboxylic acid[(9aminomethyl)]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amideExample 15 5-Chloro-1H-indole-2-carboxylic acid1(9acetylaminomethyl]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amideExample 16 5-Chloro-1H-indole-2-carboxylic acid{9-[(3-methyl-ureido)methyl]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl}-amideExample 17 5-Chloro-1H-indole-2-carboxylic acid[9-(methylsulfonylamino-methyl)].3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl}-amideExample 18{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9aza-benzocyclohepten-9yl}-aceticacid ethyl ester

5-Chloroindole-2-carboxylic acid (73 mg, 0.37 mmol, 1 eq.),(2-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-acetic acidethyl ester (93 mg, 0.37 mmol 1 eq.), and BOP (163 mg, 0.37 mmol, 1 eq.)were dissolved in 5 mL of anhydrous THF in a round bottom flask.Triethylamine was added in a single portion (0.103 mL, 74 mmol, 2 eq.)and reaction mixture stirred at room temperature for 5 hours. Thereaction mixture was then concentrated and the residue purified bypreparative TLC in 50% AcOEt/hexane affording 79 mg (50% yield) of theproduct an off-white crystalline solid. LC MS: AP+ 428/430, AP− 426/428.

Example 19{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9yl}-aceticacid

{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-aceticacid ethyl ester (10 mg, 0.023 mmol, 1 eq.) was dissolved in a mixtureof 1 mL of MeOH and 1 mL of THF and treated with 1 mL 1N NaOH. Thereaction was stirred at room temperature for 3 hrs at which time thesolvents were removed by evaporation and the residue acidified with 1NHCl. The precipitate was collected on a filter, dried and purified onpreparative TLC in 9:1 CH₂Cl₂/MeOH to afford 9 mg of the product as awhite solid. LC MS: AP+ 400/402,

Example 20 5-Chloro-1H-indole-2-carboxylic acid[9-(2-oxo-2-pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide

{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-aceticacid (80 mg) and pyrrolidine (14.2 mg) were dissolved in anhydrous THF.To that solution was added BOP and the resulting mixture treated withtriethylamine (40.5 mg). The reaction was stirred overnight at roomtemperature. The reaction was evaporated and the crude product purifiedby TLC using EtOAc as solvent to yield 68 mg of the product. LCMS: AP⁺453/455.

Example 21 5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide

{2[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-aceticacid (80 mg) was dissolved in THF (3 mL) and treated with 1.0 M BH₃/THFat room temperature. The reaction was concentrated in vacuo, dilutedwith EtOAc and washed with 1N HCl. The crude product was purified bypreparative TLC (EtOAc) to yield 27 mg of the product as a crystallinesolid. LCMS: AP⁺ 386/388.

Example 22 5-Chloro-1H-indole-2-carboxylic acidbenzo[b][1,3]dioxol-5-ylamide;

LC MS AP⁺: 315.

Example 23 5-Chloro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 343

Example 24 1H-lndole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LIC, MS AP⁺: 309

Example 25 H-lndole-2-carboxylic acid benzo[1,3]dioxol-5-ylamide

LC MS AP⁺: 281

5-Fluoro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide Example 265-Methoxy-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 339

Example 27 5-Bromo-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 387/389

Example 28 5-Methyl-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 323

Example 29 6Methoxy-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 339

Example 308-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-carboxylicacid methyl ester

LC MS AP⁺: 401

Example 318-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid

LC MS AP⁺: 387.

Example 32 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 349

Example 33 5-Chloro-1H-indole-2-carboxylic acid(9-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 343

Example 34 5-Chloro-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 373

Example 35 5-Chloro-1H-indole-2-carboxylic acid(9-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 358

Example 36 5-Chloro-1H-indole-2-carboxylic acid(9-dimethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP+: 414

Example 37 5-Chloro-1H-indole-2-carboxylic acid(9-diethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 442

Example 38 5-Chloro-1H-indole-2-carboxylic acid[9-(pyrrolidine-1-carbonyl)-3,4-1,5-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 440

Example 39 5-Chloro-1H-indole-2-carboxylic acid[9-(piperidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 454

Example 40 5-Chloro-1H-indole-2-carboxylic acid[9-(morpholine-4-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 456

Example 41 5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 430

Example 42 5-Chloro-1H-indole-2-carboxylic acid[9-(3,4-dihydroxy-pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 472

Example 43 5-Chloro-1H-indole-2-carboxylic acid(9-methoxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 387

Example 44 5-Chloro-1H-indole-2-carboxylic acid(9-carbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 386

Example 45 5-Chloro-1H-indole-2-carboxylic acid[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 469

Example 46 5-Chloro-1H-indole-2-carboxylic acid(9-acetylamino-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 400

Example 47 5-Chloro-1H-indole-2-carboxylic acid(9dimethylamino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 386

Example 48{8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylamino}-aceticacid ethyl ester LC, MS AP⁺: 444 Example 495-Chloro-1H-indole-2-carboxylic acid[9-(2,2,2-trifluoro-acetylamino)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 454

Example 50 5-Chloro-1H-indole-2-carboxylic acid(9-methanesulfonylamino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 436

Example 51 5-Chloro-1H-indole-2-carboxylic acid[9(2-chloro-acetylamino)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 435

Example 52 5-Chloro-1H-indole-2-carboxylic acid(9-diethylaminomethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 428

Example 53 5-Chloro-1H-indole-2-carboxylic acid(9-dimethylaminomethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 400

Example 54 5-Chloro1H-indole-2-carboxylic acid{9[(2-hydroxy-ethylamino)-methyl]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl}-amide

LC MS AP⁺: 416

Example 55 5-Chloro-1H-indole-2-carboxylic acid(9-piperidin-1-ylmethyl-3,4-dihydro-2H-benzo[b][4]dioxepin-7-yl)-amide

LC MS AP⁺: 440

Example 56 5-Chloro-1H-indole-2-carboxylic acid(9-morpholin-4-ylmethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

MS AP⁺: 442

Example 57 5-Chloro-1H-indole-2-carboxylic acid[9-(benzylamino-methyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 462

Example 58 5-Chloro-1H-indole-2-carboxylic acid[9(3,4-dihydroxy-pyrrolidin-1-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 458

Example 59 5-Chloro-1H-indole-2-carboxylic acid{9-[(2-methoxy-ethylamino)-methyl]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl}-amide

LC MS AP⁺: 430

Example 60 1H-lndole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 339

Example 61 5-Fluoro-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 357

Example 62 5-Methyl-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP+: 353

Example 63 5-Chloro-1H-indole-2-carboxylic acid{9-[(2-hydroxy-ethylcarbamoyl)-methyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide

LC MS AP⁺: 444

Example 64 5-Chloro-1H-indole-2-carboxylic acid[9-(2-oxo-2-piperidin-1-yl-ethyl)-6,78,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide

LC MS AP⁺: 468

Example 65 5-Chloro1H-indole-2-carboxylic acid[9-(2-morpholin-4-yl-2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide

LCMS AP⁺: 470

Example 66 5-Chloro-1H-indole-2-carboxylic acid{9-[2-(3,4-dihydroxy-pyrrolidin-yl)-2-oxo-ethyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide

LCMS: AP⁺: 486

Example 67 5-Chloro-1H-indole-2-carboxylic acid{9-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide

LCMS: AP⁺: 483

Example 683-(4-Chloro-phenyl)-N-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-acrylamide

LC MS AP⁺: 330

Example 693-(4-Chloro-phenyl)-N-(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-acrylamide

LC MS AP⁺: 360

Example 70 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 349

Example 71 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide

LC MS AP⁺: 335

Example 72 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 378/380

Example 73 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza -benzocyclohepten-2-yl)-amide

LC-MS AP⁺: 348

Example 74 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid[1,5-bis-(toluene-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl]-amide

LC MS AP⁺: 475

Example 75 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(9-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide

LC MS AP+:362

Example 76 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC, MS AP⁺: 475

Example 76 5-Chloro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide Example 785-Fluoro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin -7-yl)-amide Example 795-Methyl-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide Example 808-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid Example 81 5-Chloro-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amideExample 82 5-Chloro-1H-indole-2-carboxylic acid(9-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide Example 835-Chloro-1H-indole-2-carboxylic acid(9-diethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amideExample 84 5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 430

Example 85 5-Chloro-1H-indole-2-carboxylic acid[9-(3,4-dihydroxy-pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 472

Example 86 5-Chloro-1H-indole-2-carboxylic acid(9-methoxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 387

Example 87 5-Chloro-1H-indole-2-carboxylic acid[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 469

Example 88 5-Chloro-1H-indole-2-carboxylic acid(9-methanesulfonylamino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 436

Example 89 5-Chloro-1H-indole-2-carboxylic acid{9-[(2-hydroxy-ethylamino)-methyl]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl}-amide

LC MS AP⁺: 416

Example 90 5-Chloro-1H-indole-2-carboxylic acid[9-(3,4-dihydroxy-pyrrolidin-1-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 458

Example 91 5-Fluoro-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 357

Example 92 5-Methyl-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 353

Example 93 5-Chloro-1H-indole-2-carboxylic acid{9-[(2-hydroxy-ethylcarbamoyl)methyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide

LC MS AP⁺: 444

Example 94 5-Chloro-1H-indole-2-carboxylic acid[9-(2-oxo-2-piperidin-1-yl-ethyl)6,7,8,9-tetrahydro-5-oxa-9aza-benzocyclohepten-2-yl]-amide

LCMS AP⁺: 468

Example 95 5-Chloro-1H-indole-2-carboxylic acid[9-(2-morpholin-4-yl-2-oxo-ethyl)-6,78,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide

LCMS: AP⁺: 470

Example 96 5-Chloro-1H-indole-2-carboxylic acid{9-[2-(3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide

LCMS: AP^(+:) 486

Example 97 5-Chloro-1H-indole-2-carboxylic acid{9-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide

LCMS: AP⁺: 483

Example 983-(4-Chloro-phenyl)-N-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-acrylamide

LC MS AP⁺: 330

Example 99 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 348

Example 100 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(2,3-dihydro-benzo[b][1,4]dioxin-6-yl)-amide

LC MS AP⁺: 335

Example 101 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide

LC MS AP⁺: 378/380

Example 102 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza -benzocyclohepten-2-yl)-amide

LC MS AP⁺: 348

Example 103 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid[1,5-bis-toluene-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl]-amide

LC MS AP⁺: 656

Example 104 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid(9-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide

LC MS AP⁺: 362

Example 105 2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide

LC MS AP⁺: 475

Example 106 Methyl-3-aminosalicylate

Methyl-3-nitrosalicylat (4.93 grams, 25 mmol) dissolved in 50 mL ofmethanol was placed in a Parr bottle together with 200 mg of 10% Pd/Cand hydrogenated at room temperature at 45 psi for 2 hours. The reactionwas then filtered through celite, concentrated to dryness and theproduct dried in vacuo. Yield 4.17 gram (99% light green needles, M+168,single spot on TLC.

Example 107 3-Formylamino-2-hydroxy-benzoic acid methyl ester

To a solution of methyl-3-aminosalicylate (3.34 grams, 20 mmol) inconcentrated formic acid (20 mL) was added solid sodium formate (1.36grams, 20 mmol, 1 eq.) and the resulting suspension stirred under refluxfor 2 hours. The precipitate was filtered at room temperature and washedwith water until neutral. After drying on air, 3.595 grams (92%) lightbrown crystals were collected. M+196, M−194.

Example 1089Formyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid methyl ester

Potassium carbonate was ground and flame dried prior to each use.3-tormylamido-2-hydroxy-benzoic acid methyl ester compound (1.952 grams,10 mmol) and potassium carbonate (2.764 grams, 20 mmol, 2 eq.) wereplaced in a flask together with 100 mL of anhydrous DMF. Heated to 1200°C. for 1 hour. 1-bromo-3-chloropropane (1 mL, 10 mmol, 1 eq.) was addedto the reaction mixture in several portions at 120° C. and the reactionheated for an additional 3 hours. The reaction was monitored on TLC(ethyl acetate). After cooling, the reaction mixture was stripped to aminimal volume, diluted with water and extracted three times with ethylacetate. The combined organic portions were washed with water, brine anddried over magnesium sulfate. Filtration and solvent removal affordedcrude product as a thick brown syrup (1.78 grams) which waschromatographed on silica gel using 30% ethyl acetate in hexane aseluent. The product was obtained in 67% yield as light yellow solid.M+236.

Example 1099Formyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid methyl ester

The compound9-formyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid methyl ester (705 mg, 3 mmol) was dissolved in concentratedsulfuric acid (30 mL) and the resulting deep blue solution cooled to 00°C. in an ice bath. It was then treated with 90% fuming nitric aciddropwise (1.5 mL), allowed to warm up to room temperature and stirredfor additional 2 hours. The reaction mixture was then carefully pouredover 500 mL of ice and the pink precipitate was filtered at roomtemperature, washed thoroughly with water and dried in vacuo. The crudeproduct was recrystallized from boiling acetonitrile. Yield 702 mg (83%)light yellow crystals, M−280.

Example 1102-Nitro-6,7,8,9tetrahydro-5-oxa-9-aza-benzocyclohepten-4-carboxylic acidmethyl ester

The previously prepared nitroamide9-formyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid methyl ester (4.76 grams, 17 mmol) was suspended in 1N HCl andheated to 100° C. for 2 hours. After cooling to room temperature, the pHof the reaction mixture was adjusted to 12 with 1N NaOH. The precipitateformed was extracted with ethyl acetate. The latter was dried overanhydrous magnesium sulfate, filtered and evaporated.

Example 1112-Amino-6,7,8,9tetrahydro-5-oxa-aza-benzocyclohepten-4-carboxylic acidmethyl ester

To a 1.51 gram (6 mmol) of the nitro methyl ester compound2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid methyl ester in a 100 mL of 1:1 mixture of methanol:THF, a 50 mg of10% Pd/C and solid ammonium formate (1.89 gram, 30 mmol, 5 eq.) wasadded carefully under nitrogen. The reaction mixture was stirred at roomtemperature in a capped vial for 2 hours, dilute with 300 mLdiethylether and through celite. The solvent removal afforded 1.71 gramsof crude product, which was flash chromatographed on silica gel in ethylacetate. Yield 1.29 grams clear syrup (96%), M+223.

Example 1122-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptane-4-carboxylicacid methyl ester M+400/402, M−398/400. Example 1132-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9tetrahydro-5-oxa-9aza-benzocycloheptene-4-carboxylicacid M−385/387. Example 114 5-Chloro-1H-indole-2-carboxylic acid(4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-2-yl)-amideM+372/374, M−370/372. Example 115N,N′-ditosyl-4-nitro-o-phenylenediamine

4-nitro-o-phenylenediamine (15.4 grams, 100 mmol) was dissolved inanhydrous pyridine (70 mL) at 45° C. p-Toluenesulfonyl chloride wasadded to the reaction mixture in 5 gram portions over the period of 30minutes. The reaction was then heated to, 100° C. for 4 hours. Aftercooling to room: temperature, the mixture was poured into ice/water andthis was extracted 3 times with methylene chloride.

The combined organic portions were washed with water and brine and driedover anhydrous sodium sulfate. Filtration and concentration affordedcrude product, which was triturated with hot ethanol to give 32.5 gramsof product as yellow powder (70%). M+462.

Example 1167-Nitro1,5-bis-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine

The 3-neck round bottom flask equipped with reflux condenser, nitrogeninlet and mechanical stirrer was flame dried and cooled in a stream ofdry nitrogen.

The flask was then charged with 32 mL of anhydrous n-butanol and sodiummetal flakes (0.46 grams, 20 mmol, 2 eq.). This was stirred at roomtemperature until all the metal dissolved and evolution of hydrogen gasceased. The solid ditosylate N,N′-ditosyl-4-nitro-o-phenylenediamine wasthen added in portions and the solution heated to 125° C. until anorange thick paste formed. The 1,3-dibromopropane (1.52 mL, 15 mmol, 1.5eq.) was added dropwise as a solution in 5 mL of anhydrous n-butanol andthe solution heated to 125° C. overnight. The reaction was monitored byTLC. Another equivalent of 1,3-dibromopropane was added and the solutionheated for an additional 12 hours. The reaction was cooled to roomtemperature, concentrated in vacuo and the residue combined wit 100 mLof 3% NaOH and refluxed for one hour. The hot solution was filtered, thefilter cake washed thoroughly with warm 1% NaOH and water until neutral.The crude product was dried in vacuo and recrystallized form boilingacetic acid. Yield 1.238 grams (23%) of yellow powder. M+502, M−345(loss of Ts).

Example 1177-Amino-1,5-bis-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-6-1H-benzo[b][1,4]diazepine

The ditosylate 7-Nitro1,5-bis-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine(502 mg, 1 mmol), 10% Pd/C (20 mg) and ammonium formate (315 mg, 5 mmol,5 eq.) was dissolved in a mixture of 5 mL of methanol and 5 mL THF andstirred in a capped flask at room temperature for 3 hours. The reactionmixture was then diluted with 60 mL of diethylether, filtered throughcelite and the filtrate concentrated. The crude product was dried invacuo to give 412 mg (87%) of white powder, M+489. This was used withoutfurther purification.

Example 118 5-chloro-1H-indole-2-carboxylic acid[1,5-bis-(toluene-4-sulfonyl)-2,3,4-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl]amideM+652/650, M−648,650. Example 1192-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid[1,5-bis-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl]-amide

M+655/657, M−499 (loss of Ts group).

1. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein n is 0, 1, 2, 3or 4; m is 0, 1, 2, 3 or 4; Z is oxygen or sulfur; R¹ is

wherein the dashed lines represent optional double bonds; a is 1, 2 or3; each R² is independently hydrogen, halo, hydroxy, amino, nitro,(C₁-C₆)alkoxy, cyano, C(O)H or (C₁-C₆)alkyl optionally substituted byone to three fluoro atoms; R³ is hydrogen, halo, cyano, (C₁-C₆)alkyl or(C₁-C₃)alkynyl; R⁴ is hydrogen, halo, cyano or (C₁-C₆)alkyl; R⁵ is

wherein the dashed lines represent optional double bonds; A, B and E areeach independently nitrogen or CR¹⁵; X and Y are each independently CH₂,oxygen, S(O)_(d) wherein d is 0, 1 or 2; nitrogen or NR¹⁶; R⁸, R⁹, R¹⁰and R¹¹ are each independently hydrogen or (C₁-C₆)alkyl; R¹² ishydrogen, HC(O)(C₀-C₆)alkyl, carboxy(C₀-C₃)alkyl,R¹⁷R¹⁸N—C(O)—(C₀-C₃)alkyl, hydroxy(C₁-C₃)alkyl, R¹⁷(C₁-C₃)alkyl,R¹⁷R¹⁸N(C₀-C₃)alkyl, (C₁-C₆)alkyl-C(O)—NH, (C₆-C₁₀)aryl-C(O)—NH,(C₆-C₁₀)aryl(C₁-C₆)alkyl-C(O)—NH, (C₂-C₉)heteroaryl(C₁-C₅)alkyl-C(O)—NH,(C₁-C₆)alkylaminocarbonylamino, (C₆-C₁₀)arylaminocarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminocarbonylamino,(C₁-C₆)alkylsulfonylamino, (C₆-C₁₀)aryl(C₁-C₆)alkylsulfonylamino,(C₂-C₉)heteroarylsulfonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylN((C₁-C₆)alkyl), (C₆-C₁₀)aryl(C₁-C₆)alkylsulfonyl N((C₁-C₆)alkyl),(C₂-C₉)heteroarylsulfonyl N((C₁-C₆)alkyl),(C₂-C₉)heteroaryl(C₁-C₆)alkylsulfonyl N((C₁-C₆)akyl),(C₃-C₇)cycloalkylamino, ((C₃-C₇)cycloalkyl)₂amino,(C₃-C₇)cycloalkylcarbonylamino,(C₆-C₁₀)aryl(C₃-C₇)cycloalkylcarbonylamino,(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylcarbonylamino,(C₃-C₇)cycloalkylaminocarbonylamino,(C₆-C₁₀)aryl(C₃-C₇)cycloalkylaminocarbonylamino,(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylaminocarbonylamino,(C₃-C₇)cycloalkylsulfonylamino,(C₆-C₁₀)aryl(C₃-C₇)cycloalkylsulfonylamino,(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylsulfonylamino,(C₃-C₇)cycloalkylsulfonyl N((C₃-C₇)cycloalkyl),(C₆-C₁₀)aryl(C₃-C₇)cycloalkylsulfonyl N((C₃-C₇)cycloalkyl,(C₂-C₉)heteroarylsulfonyl N((C₃-C₇)cycloalkyl),(C₂-C₉)heteroaryl(C₃-C₇)cycloalkylsulfonyl N((C₃-C₇)cycloalkyl),(C₁-C₆)alkyl S(O)_(c), (C₃-C₇)cycloalkyl S(O)_(c),(C₆-C₁₀)aryl(C₁-C₆)alkyl S(O)_(c), (C₆-C₁₀)aryl S(O)_(c),(C₁-C₆)alkylamino S(O)_(c), (C₁-C₆)arylamino S(O)_(c),(C₆-C₁₀)arylC₁-C₆)alkylamino S(O)_(c) wherein c is 0, 1 or 2; R¹³ ishydrogen or (C₁-C₆)alkyl; R¹⁴ is hydrogen, hydroxy, (C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy or NR¹⁷R¹⁸; R¹⁵ is hydrogen,(C₁-C₆)alkylcarbonylcarboxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkylpiperazinylcarbonyl or piperidinylcarbonyl; R¹⁶ is hydrogen, HCO,(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,piperidinyl(C₁-C₆)alkylcarbonyl; (C₁-C₆)acyl; piperidinylcarbonyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkylcarbonyl ormorpholinyl(C₁-C₆)alkylcarbonyl; R¹⁷ and R¹⁸ are each independentlyhydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkyl and(C₂-C₉)heteroaryl(C₁-C₆)alkyl.
 2. A compound of claim 1, wherein R² is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms.
 3. Acompound of claim 1, wherein n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and Zis oxygen.
 4. A compound according to claim 1, wherein R⁵ is

wherein A, B and E are CR¹⁵; X is oxygen or nitrogen; Y is oxygen orNR¹⁶; R¹² is hydrogen, (C₁-C₆)alkyl, hydroxy(C₁-C₃)alkyl or carboxy; R¹⁵is hydrogen, (C₁-C₆)alkylcarbonylcarboxy, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkyl piperazinylcarbonyl or piperidinylcarbonyl; R¹⁶ is HCO,(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,piperidinyl(C₁-C₆)alkylcarbonyl; (C₁-C₆)acyl; piperidinylcarbonyl(C₁-C₆)alkyl, hydroxy((C₁-C₆)alkyl, halo(C₁-C₆)alkylcarbonyl ormorpholinyl(C₁-C₆)alkylcarbonyl.
 5. A compound of claim 1, wherein R⁵ is

wherein A is CR¹⁵; B and E are each independently CR¹⁵ or nitrogen; andX and Y are each independently nitrogen or CH₂.
 6. A compound of claim1, wherein R⁵ is

wherein A is CR¹⁵; B and E are each independently CR¹⁵ or nitrogen; andX and Y are each independently nitrogen or CH₂.
 7. A compound of claim1, wherein R¹ is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms; n is0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R⁵ is

wherein A, B and E are CR¹⁵; X is oxygen or nitrogen; Y is oxygen orNR¹⁶; R¹² is H, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl or carboxy; R¹⁵ ishydrogen, (C₁-C₆)alkylcarbonylcarboxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkylpiperazinylcarbonyl or piperidinylcarbonyl; R¹⁶ is HCO, (C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,piperidinyl(C₁-C₆)alkylcarbonyl; (C₁-C₆)acyl; piperidinylcarbonyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, halo(C₁-C₆)alkylcarbonyl ormorpholinyl(C₁-C₆)alkylcarbony.
 8. A compound of claim 1, wherein R¹ is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms; n is0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R⁵ is

wherein A is CR¹⁵; B and E are each independently CR¹⁵ or nitrogen; andX and Y are each independently nitrogen or CH₂.
 9. A compound of claim1, wherein R¹ is

wherein a is 1 or 2; and each R² is independently halo, amino or(C₁-C₆)alkyl optionally substituted by one to three fluoro atoms; n is0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R⁵ is

wherein A is CR¹⁵; B and E are each independently CR¹⁵ or nitrogen; andX and Y are each independently nitrogen or CH₂.
 10. A compound of claim1, wherein said compound is selected from the group consisting of:5-Chloro-1H-indole-2-carboxylic acid(4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid(9-methanesulfonylamino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;{8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylamino}-aceticacid ethyl ester;{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-4-hydroxymethyl-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-aceticacid: 5-Chloro-1H-indole-2-carboxylic acid(9-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-aceticacid; 5-Methyl-1H-indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid{9-[2-(3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl-]6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;5-Chloro-1H-indole-2-carboxylic acid[4-(piperidine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;5-Chloro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-amide;5-Fluoro-1H-indole-2-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;5-Chloro-1H-indole-2-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid(9-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza -benzocyclohepten-2-yl)-amide;2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid; 5-Chloro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl) -amide;5-Methyl-1H-indole-2-carboxylic acid(6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid(9-dimethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid[9-(2-oxo-2-pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;5-Bromo-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Methyl-1H-indole-2-carboxylic acid(2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide;8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylicacid: 5-Methyl-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid[9-(3,4-dihydroxy-pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;5-Chloro-1H-indole-2-carboxylic acid[4-(4-methyl-piperazine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;1H-Indole-2-carboxylic acid(9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide; 1H-Indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid-[9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;5-Fluoro-1H-indole-2-carboxylic acid(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;5-Chloro-1H-indole-2-carboxylic acid{9-[(2-hydroxy-ethylcarbamoyl)-methyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylicacid methyl ester; 5-Chloro-1H-indole-2-carboxylic acid[9-(2-hydroxy-ethyl)-4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;1H-Indole-2-carboxylic acid(2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide; and5-Fluoro-1H-indole-2-carboxylic acid(2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide.
 11. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier ordiluent.
 12. A method of treating atherosclerosis, diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, cataracts, hypercholesterolemia, hypertriglyceridemia,hyperlipidemia, hyperglycemia, hypertension, tissue ischemia ormyocardial ischemia in a mammal, the method comprising administering tosaid mammal suffering from atherosclerosis, diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, cataracts, hypercholesterolemia, hypertriglyceridemia,hyperlipidemia, hyperglycemia, hypertension, tissue ischemia ormyocardial ischemia a compound of claim 1, a pharmaceutically acceptablesalt thereof or a pharmaceutical composition comprising said compound ofclaim
 1. 13. A method of inhibiting glycogen phosphorylase in a mammal,the method comprising administering to said mammal in need of glycogenphosphorylase ihibition a compound of claim 1, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition comprising saidcompound of claim
 1. 14. A method of treating diabetes, insulinresistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, cataracts, hyperglycemia, hypercholesterolemia,hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis ortissue ischemia, the method comprising the step of administering to apatient suffering from diabetes, insulin resistance, diabeticneuropathy, diabetic nephropathy, diabetic retinopathy, cataracts,hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia,hyperlipidemia, atherosclerosis or tissue ischemia a compound of claim 1or a pharmaceutically acceptable salt thereof in combination with atleast one additional compound useful for the treatment of diabetes,insulin resistance, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, cataracts, hyperglycemia, hypercholesterolemia,hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis ortissue ischemia.